Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof

ABSTRACT

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a SGLT-2 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprisingfixed dose combinations of a SGLT-2 inhibitor drug and a partner drug,processes for the preparation thereof, and their use to treat certaindiseases. In a more detailed aspect, the present invention relates tooral solid dosage forms for fixed dose combination (FDC) of a selectedSGLT-2 inhibitor drug and a certain partner drug.

In addition the invention relates to a process for the preparation ofsuch a pharmaceutical dosage form. In addition the invention relates tothe use of the pharmaceutical composition and of the pharmaceuticaldosage form in the treatment and/or prevention of selected diseases andmedical conditions, in particular of one or more conditions selectedfrom type 1 diabetes mellitus, type 2 diabetes mellitus, impairedglucose tolerance, impaired fasting blood glucose and hyperglycemiainter alia. Furthermore the present invention relates to methods oftreating and/or preventing of such diseases and medical conditionswherein a pharmaceutical composition or pharmaceutical dosage formaccording to the invention is administered to a patient in need thereof.

BACKGROUND OF THE INVENTION

Type 2 diabetes is an increasingly prevalent disease that due to a highfrequency of complications leads to a significant reduction of lifeexpectancy. Because of diabetes-associated microvascular complications,type 2 diabetes is currently the most frequent cause of adult-onset lossof vision, renal failure, and amputations in the industrialized world.In addition, the presence of type 2 diabetes is associated with a two tofive fold increase in cardiovascular disease risk.

After long duration of disease, most patients with type 2 diabetes willeventually fail on oral therapy and become insulin dependent with thenecessity for daily injections and multiple daily glucose measurements.

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated thatintensive treatment with metformin, sulfonylureas or insulin resulted inonly a limited improvement of glycemic control (difference in HbA1c˜0.9%). In addition, even in patients within the intensive treatment armglycemic control deteriorated significantly over time and this wasattributed to deterioration of n-cell function. Importantly, intensivetreatment was not associated with a significant reduction inmacrovascular complications, i.e. cardiovascular events. Therefore manypatients with type 2 diabetes remain inadequately treated, partlybecause of limitations in long term efficacy, tolerability and dosinginconvenience of existing antihyperglycemic therapies.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors.

The high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and macrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications) in patients with type 2 diabetes.

Therefore, there is an unmet medical need for methods, medicaments andpharmaceutical compositions with a good efficacy with regard to glycemiccontrol, with regard to disease-modifying properties and with regard toreduction of cardiovascular morbidity and mortality while at the sametime showing an improved safety profile.

SGLT2 inhibitors inhibitors represent a novel class of agents that arebeing developed for the treatment or improvement in glycemic control inpatients with type 2 diabetes. Glucopyranosyl-substituted benzenederivative are described in the prior art as SGLT2 inhibitors, forexample in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO2008/049923, WO 2008/055870, WO 2008/055940. Theglucopyranosyl-substituted benzene derivatives are proposed as inducersof urinary sugar excretion and as medicaments in the treatment ofdiabetes.

Renal filtration and reuptake of glucose contributes, among othermechanisms, to the steady state plasma glucose concentration and cantherefore serve as an antidiabetic target. Reuptake of filtered glucoseacross epithelial cells of the kidney proceeds via sodium-dependentglucose cotransporters (SGLTs) located in the brush-border membranes inthe tubuli along the sodium gradient. There are at least 3 SGLT isoformsthat differ in their expression pattern as well as in theirphysico-chemical properties. SGLT2 is exclusively expressed in thekidney, whereas SGLT1 is expressed additionally in other tissues likeintestine, colon, skeletal and cardiac muscle. SGLT3 has been found tobe a glucose sensor in interstitial cells of the intestine without anytransport function. Potentially, other related, but not yetcharacterized genes, may contribute further to renal glucose reuptake.Under normoglycemia, glucose is completely reabsorbed by SGLTs in thekidney, whereas the reuptake capacity of the kidney is saturated atglucose concentrations higher than 10 mM, resulting in glucosuria(“diabetes mellitus”). This threshold concentration can be decreased bySGLT2-inhibition. It has been shown in experiments with the SGLTinhibitor phlorizin that SGLT-inhibition will partially inhibit thereuptake of glucose from the glomerular filtrate into the blood leadingto a decrease in blood glucose concentrations and to glucosuria.

AIM OF THE PRESENT INVENTION

The aim of the present invention is to provide a pharmaceuticalcomposition comprising a SGLT2 inhibitor and a partner drug which hashigh content uniformity for the SGLT2 inhibitor and the partner drug.

Another aim of the present invention is to provide a pharmaceuticalcomposition comprising a SGLT2 inhibitor and a partner drug which hasvery high drug load for the partner drug and very low drug load for theSGLT2 inhibitor.

Another aim of the invention is to provide a pharmaceutical compositioncomprising a SGLT2 inhibitor and a partner drug which allows aneffective production with regard to time and costs of pharmaceuticaldosage forms.

Another aim of the present invention is to provide a pharmaceuticalcomposition comprising a SGLT-2 inhibitor and a partner drug whichavoids or reduces sticking and capping during the production process ofthe composition.

Another aim of the present invention is to provide a pharmaceuticalcomposition comprising a SGLT-2 inhibitor and a partner drug whichavoids or reduce filming during the production process of thecomposition.

Another aim of the present invention is to provide a pharmaceuticaldosage form comprising a SGLT-2 inhibitor and a partner drug which hasan acceptable size.

Another aim of the invention is to provide a pharmaceutical dosage formcomprising a SGLT-2 inhibitor and a partner drug which has a shortdisintegration time, which has good dissolution properties and/or whichenables a high bioavailability of the SGLT-2 inhibitor in a patient.

Another aim of the invention it to provide a pharmaceutical compositionand a pharmaceutical dosage form, each comprising a SGLT2 inhibitor anda partner drug, and a method for preventing, slowing progression of,delaying or treating a metabolic disorder, in particular of type 2diabetes mellitus.

A further aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, and a method for improving glycemiccontrol in a patient in need thereof, in particular in patients withtype 2 diabetes mellitus.

Another aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, and a method for improving glycemiccontrol in a patient with insufficient glycemic control.

Another aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, and a method for preventing, slowing ordelaying progression from impaired glucose tolerance (IGT), impairedfasting blood glucose (IFG), insulin resistance and/or metabolicsyndrome to type 2 diabetes mellitus.

Yet another aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, and a method for preventing, slowingprogression of, delaying or treating of a condition or disorder from thegroup consisting of complications of diabetes mellitus.

A further aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, and a method for reducing the weight orpreventing an increase of the weight in a patient in need thereof.

Another aim of the present invention is to provide a pharmaceuticalcomposition and a pharmaceutical dosage form, each comprising a SGLT2inhibitor and a partner drug, with a high efficacy for the treatment ofmetabolic disorders, in particular of diabetes mellitus, impairedglucose tolerance (IGT), impaired fasting blood glucose (IFG), and/orhyperglycemia, which has good to very good pharmacological and/orpharmacokinetic and/or physicochemical properties.

Another aim of the present invention is to provide a process for thepreparation of a pharmaceutical dosage form according to the inventionwhich is effective in costs and/or time.

Further aims of the present invention become apparent to the one skilledin the art by description hereinbefore and in the following and by theexamples.

SUMMARY OF THE INVENTION

In one aspect the present invention provides a pharmaceuticalcomposition comprising a SGLT-2 inhibitor and a partner drug as a activepharmaceutical ingredients and one or more excipients. In one aspect, apharmaceutical compositions according to the invention is a solidpharmaceutical composition, for example a solid pharmaceuticalcomposition for oral administration.

In one aspect, partner drugs to be combined with the SGLT-2 inhibitorwithin the pharmaceutical compositions according to this invention arebiguanides (e.g. metformin such as metformin hydrochloride).

A preferred partner drug within the meaning of this invention ismetformin, particularly metformin hydrochloride (1,1-dimethylbiguanidehydrochloride or metformin HCl).

In general, pharmaceutical excipients which may be used may be selectedfrom the group consisting of one or more fillers, one or more binders ordiluents, one or more lubricants, one or more disintegrants, and one ormore glidants, one or more film-coating agents, one or moreplasticizers, one or more pigments, and the like.

The pharmaceutical compositions (tablets) of this invention compriseusually a binder.

In more detail, the pharmaceutical compositions (tablets) of thisinvention comprise usually one or more fillers (e.g. D-mannitol, cornstarch and/or pregelatinized starch and/or microcrystalline cellulose),a binder (e.g. copovidone), a lubricant (e.g. magnesium stearate, sodiumstearyl fumarate), and a glidant (e.g. colloidal anhydrous silica).

Suitably the pharmaceutical excipients used within this invention areconventional materials such as D-mannitol, corn starch, microcrystallinecellulose, pregelatinized starch as a filler, copovidone as a binder,magnesium stearate or sodium stearyl fumarate as a lubricant, colloidalanhydrous silica as a glidant, hypromellose as a film-coating agent,propylene glycol as a plasticizer, titanium dioxide, iron oxidered/yellow/black or mixture thereof as a pigment, and talc, etc.

A typical composition according to the present invention comprises thebinder copovidone (also known as copolyvidone or Kollidon VA64).

Further, a typical composition according to the present inventioncomprises the filler corn starch, the binder copovidone, the lubricantmagnesium stearate, and the glidant colloidal anhydrous silica.

Further, a typical composition according to the present inventioncomprises the filler microcrystalline cellulose, the binder copovidone,the lubricant magnesium stearate or sodium stearyl fumarate, and theglidant colloidal anhydrous silica and optionally the desintegrantcrospovidone or croscarmellose sodium.

Thus, in particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a SGLT-2 inhibitor, metforminhydrochloride and one or more pharmaceutical excipients, particularlyone or more fillers, one or more binders, one or more glidants, and/orone or more lubricants.

In more particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a SGLT-2 inhibitor, metforminhydrochloride, copovidone as binder and one or more furtherpharmaceutical excipients.

Typical pharmaceutical compositions of this invention may comprise inthe SGLT-2 inhibitor portion (% by weight of total SGLT-2 inhibitorportion):

 0.1-10% SGLT-2 inhibitor,  0.1-3% SGLT-2 inhibitor, 0.4-2.2% SGLT-2inhibitor, or 0.1-2.11%  SGLT-2 inhibitor

Typical pharmaceutical compositions of this invention may also comprisein the SGLT-2 inhibitor portion (% by weight of total SGLT-2 inhibitorportion):

 0.1-10% SGLT-2 inhibitor,  0.1-3% SGLT-2 inhibitor, 0.4-2.2% SGLT-2inhibitor, or 0.1-2.12%  SGLT-2 inhibitor.

Typical pharmaceutical compositions of this invention may comprise oneor more of the following amounts (% by weight of total coated tabletmass):

0.1-2.11%  SGLT-2 inhibitor,  47-88% metformin HCl, 3.9-8.3% binder(e.g. copovidone), 2.3-8.0% filler 1 (e.g. corn starch),  0-4.4% filler2 (e.g. pregelatinized starch),  0-33% filler 3 (e.g. D-mannitol),0.7-1.5% lubricant (e.g. magnesium stearate), 0.05-0.5%  glidant (e.g.colloidal anhydrous silica), 0.00-3.0%  desintegrant (e.g. crospovidoneor croscarmellose sodium).

Typical pharmaceutical compositions of this invention may comprise oneor more of the following amounts (% by weight of total coated tabletmass):

0.1-2.12%  SGLT-2 inhibitor,  47-88% metformin HCl, 3.9-8.3% binder(e.g. copovidone), 2.3-8.0% filler 1 (e.g. corn starch),  0-4.4% filler2 (e.g. pregelatinized starch),  0-33% filler 3 (e.g. D-mannitol),0.7-1.5% lubricant (e.g. magnesium stearate), 0.05-0.5%  glidant (e.g.colloidal anhydrous silica), 0.00-3.0%  desintegrant (e.g. crospovidoneor croscarmellose sodium).

In one embodiment, the FDC formulations are chemically stable and eithera) display similarity of in-vitro dissolution profiles and/or arebioequivalent to the free combination, or b) allow to adjust thein-vitro and in-vivo performance to desired levels. In a preferredembodiment the invention relates to chemically stable FDC formulationsmaintaining the original dissolution profiles of corresponding monotablets of each individual entity, with a reasonable tablet size.

In one embodiment, a pharmaceutical composition of this invention isproduced using fluid bed granulation.

Further details about the FDC formulations of this invention, e.g. theingredients, ratio of ingredients (such as e.g. ratio of SGLT-2inhibitor, metformin hydrochloride,and/or excipients), particularly withrespect to special dosage forms (tablets) used within this invention aswell as their preparation, become apparent to the skilled person fromthe disclosure hereinbefore and hereinafter (including by way of examplethe following examples).

Preferably the SGLT2 inhibitor is selected from aglucopyranosyl-substituted benzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugof one of the beforementioned SGLT2 inhibitors.

In the above glucopyranosyl-substituted benzene derivatives of theformula (I) the following definitions of the substituents are preferred.

Preferably R¹ denotes chloro or cyano; in particular chloro.

Preferably R² denotes H.

Preferably R³ denotes ethyl, cyclopropyl, ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even morepreferably R³ denotes cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxyor (S)-tetrahydrofuran-3-yloxy. Most preferably R³ denotes ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

Preferred glucopyranosyl-substituted benzene derivatives of the formula(I) are selected from the group of compounds (I.1) to (I.11):

Even more preferred glucopyranosyl-substituted benzene derivatives ofthe formula (I) are selected from the compounds (I.6), (I.7), (I.8),(I.9) and (I.11). Even more preferred glucopyranosyl-substituted benzenederivatives of the formula (I) are selected from the compounds (I.8) and(I.9), or a crystalline form (I.9X) of compound (I.9).

The pharmaceutical compositions according to the invention allow a highcontent uniformity and an effective production with regard to time andcosts of pharmaceutical dosage forms, such as tablets and capsules.Furthermore, in one embodiment, these pharmaceutical dosage forms are inparticular tablets.

Therefore in another aspect the present invention provides apharmaceutical dosage form comprising a pharmaceutical compositionaccording to the invention. In one aspect, the pharmaceutical dosageform according to the invention is a solid pharmaceutical dosage form,for example a solid pharmaceutical dosage form for oral administration.

In another aspect, the present invention provides a process for thepreparation of a pharmaceutical dosage form according to the inventioncomprising one or more granulation processes wherein the activepharmaceutical ingredient together with one or more excipients isgranulated.

It can be found that a pharmaceutical composition comprising a SGLT2inhibitor and partner drug as defined hereinafter can advantageously beused for preventing, slowing progression of, delaying or treating ametabolic disorder, in particular for improving glycemic control inpatients. This opens up new therapeutic possibilities in the treatmentand prevention of type 2 diabetes mellitus, overweight, obesity,complications of diabetes mellitus and of neighboring disease states.

Therefore, in a first aspect the present invention provides a method forpreventing, slowing the progression of, delaying or treating a metabolicdisorder selected from the group consisting of type 1 diabetes mellitus,type 2 diabetes mellitus, impaired glucose tolerance (IGT), impairedfasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia,overweight, obesity and metabolic syndrome in a patient in need thereofcharacterized in that a pharmaceutical composition or a pharmaceuticaldosage form of the present invention is administered to the patient.

According to another aspect of the invention, there is provided a methodfor improving glycemic control and/or for reducing of fasting plasmaglucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof characterized in that apharmaceutical composition or a pharmaceutical dosage form of thepresent invention is administered to the patient.

The pharmaceutical composition according to this invention may also havevaluable disease-modifying properties with respect to diseases orconditions related to impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the invention, there is provided a methodfor preventing, slowing, delaying or reversing progression from impairedglucose tolerance (IGT), impaired fasting blood glucose (IFG), insulinresistance and/or from metabolic syndrome to type 2 diabetes mellitus ina patient in need thereof characterized in that a pharmaceuticalcomposition or a pharmaceutical dosage form of the present invention isadministered to the patient.

As by the use of a pharmaceutical composition according to thisinvention, an improvement of the glycemic control in patients in needthereof is obtainable, also those conditions and/or diseases related toor caused by an increased blood glucose level may be treated.

According to another aspect of the invention, there is provided a methodfor preventing, slowing the progression of, delaying or treating of acondition or disorder selected from the group consisting ofcomplications of diabetes mellitus such as cataracts and micro- andmacrovascular diseases, such as nephropathy, retinopathy, neuropathy,tissue ischaemia, diabetic foot, arteriosclerosis, myocardialinfarction, accute coronary syndrome, unstable angina pectoris, stableangina pectoris, stroke, peripheral arterial occlusive disease,cardiomyopathy, heart failure, heart rhythm disorders and vascularrestenosis, in a patient in need thereof characterized in that apharmaceutical composition or a pharmaceutical dosage form of thepresent invention is administered to the patient. In particular one ormore aspects of diabetic nephropathy such as hyperperfusion, proteinuriaand albuminuria may be treated, their progression slowed or their onsetdelayed or prevented. The term “tissue ischaemia” particularly comprisesdiabetic macroangiopathy, diabetic microangiopathy, impaired woundhealing and diabetic ulcer. The terms “micro- and macrovasculardiseases” and “micro- and macrovascular complications” are usedinterchangeably in this application.

By the administration of a pharmaceutical composition according to thisinvention and due to the activity of the SGLT2 inhibitor excessive bloodglucose levels are not converted to insoluble storage forms, like fat,but excreted through the urine of the patient. Therefore, no gain inweight or even a reduction in body weight is the result.

According to another aspect of the invention, there is provided a methodfor reducing body weight or preventing an increase in body weight orfacilitating a reduction in body weight in a patient in need thereofcharacterized in that a pharmaceutical composition or a pharmaceuticaldosage form of the present invention is administered to the patient.

The pharmacological effect of the SGLT2 inhibitor in the pharmaceuticalcomposition according to this invention is independent of insulin.Therefore, an improvement of the glycemic control is possible without anadditional strain on the pancreatic beta cells. By an administration ofa pharmaceutical composition according to this invention a beta-celldegeneration and a decline of beta-cell functionality such as forexample apoptosis or necrosis of pancreatic beta cells can be delayed orprevented. Furthermore, the functionality of pancreatic cells can beimproved or restored, and the number and size of pancreatic beta cellsincreased. It may be shown that the differentiation status andhyperplasia of pancreatic beta-cells disturbed by hyperglycemia can benormalized by treatment with a pharmaceutical composition according tothis invention.

According to another aspect of the invention, there is provided a methodfor preventing, slowing, delaying or treating the degeneration ofpancreatic beta cells and/or the decline of the functionality ofpancreatic beta cells and/or for improving and/or restoring thefunctionality of pancreatic beta cells and/or restoring thefunctionality of pancreatic insulin secretion in a patient in needthereof characterized in that a pharmaceutical composition or apharmaceutical dosage form of the present invention is administered tothe patient.

By the administration of a pharmaceutical composition according to thepresent invention, an abnormal accumulation of fat in the liver may bereduced or inhibited. Therefore, according to another aspect of thepresent invention, there is provided a method for preventing, slowing,delaying or treating diseases or conditions attributed to an abnormalaccumulation of liver fat in a patient in need thereof characterized inthat an SGLT2 inhibitor as defined hereinbefore and hereinafter isadministered to the patient. Diseases or conditions which are attributedto an abnormal accumulation of liver fat are particularly selected fromthe group consisting of general fatty liver, non-alcoholic fatty liver(NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-inducedfatty liver, diabetic fatty liver, alcoholic-induced fatty liver ortoxic fatty liver.

As a result thereof, another aspect of the invention provides a methodfor maintaining and/or improving the insulin sensitivity and/or fortreating or preventing hyperinsulinemia and/or insulin resistance in apatient in need thereof characterized in that a pharmaceuticalcomposition or a pharmaceutical dosage form of the present invention isadministered to the patient.

According to another aspect of the invention there is provided the useof a pharmaceutical composition or a pharmaceutical dosage form of thepresent invention for the manufacture of a medicament for

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder selected from the group consisting of type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance (IGT), impaired fasting blood glucose (IFG),        hyperglycemia, postprandial hyperglycemia, overweight, obesity        and metabolic syndrome; or    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c; or    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance (IGT), impaired fasting blood glucose        (IFG), insulin resistance and/or from metabolic syndrome to type        2 diabetes mellitus; or    -   preventing, slowing the progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus such as cataracts and micro-        and macrovascular diseases, such as nephropathy, retinopathy,        neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis,        myocardial infarction, accute coronary syndrome, unstable angina        pectoris, stable angina pectoris, stroke, peripheral arterial        occlusive disease, cardiomyopathy, heart failure, heart rhythm        disorders and vascular restenosis; or    -   reducing body weight or preventing an increase in body weight or        facilitating a reduction in body weight; or    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or restoring the        functionality of pancreatic insulin secretion; or    -   preventing, slowing, delaying or treating diseases or conditions        attributed to an abnormal accumulation of liver fat; or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;

in a patient in need thereof characterized in that the SGLT2 inhibitoris administered, as defined hereinbefore and hereinafter.

According to another aspect of the invention, there is provided the useof a pharmaceutical composition or a pharmaceutical dosage form of thepresent invention according to the present invention for the manufactureof a medicament for a therapeutic and preventive method as describedhereinbefore and hereinafter.

Definitions

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor according to thepresent invention. An “active ingredient is also sometimes referred toherein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The term “obesity” is defined as the condition wherein the individualhas a BMI equal to or greater than 30 kg/m². According to a WHOdefinition the term obesity may be categorized as follows: the term“class I obesity” is the condition wherein the BMI is equal to orgreater than 30 kg/m² but lower than 35 kg/m²; the term “class IIobesity” is the condition wherein the BMI is equal to or greater than 35kg/m² but lower than 40 kg/m²; the term “class III obesity” is thecondition wherein the BMI is equal to or greater than 40 kg/m².

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference 85 cm in men and 90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 110 mg/dL (6.11 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 110 mg/dL (6.11 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range of 60 to 115mg/dL (3.3 to 6.3 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/I.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(SuppL1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(SuppL1): A459), the insulin/C-peptide secretion after an oral glucosetolerance test or a meal tolerance test, or by employing a hyperglycemicclamp study and/or minimal modeling after a frequently sampledintravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest2001, 31: 380-81).

The term “pre-diabetes” is the condition wherein an individual ispre-disposed to the development of type 2 diabetes. Pre-diabetes extendsthe definition of impaired glucose tolerance to include individuals witha fasting blood glucose within the high normal range 100 mg/dL (J. B.Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia(elevated plasma insulin concentration). The scientific and medicalbasis for identifying pre-diabetes as a serious health threat is laidout in a Position Statement entitled “The Prevention or Delay of Type 2Diabetes” issued jointly by the American Diabetes Association and theNational Institute of Diabetes and Digestive and Kidney Diseases(Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1st degree relative with adiagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can beconfirmed in these individuals by calculating the HOMA-IR score. For thepurpose of this invention, insulin resistance is defined as the clinicalcondition in which an individual has a HOMA-IR score >4.0 or a HOMA-IRscore above the upper limit of normal as defined for the laboratoryperforming the glucose and insulin assays.

The term “type 2 diabetes” is defined as the condition in which asubject has a fasting blood glucose or serum glucose concentrationgreater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucosevalues is a standard procedure in routine medical analysis. If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach. In a glucosetolerance test 75 g of glucose are administered orally to the patientbeing tested after 10-12 hours of fasting and the blood sugar level isrecorded immediately before taking the glucose and 1 and 2 hours aftertaking it. In a healthy subject, the blood sugar level before taking theglucose will be between 60 and 110 mg per dL of plasma, less than 200 mgper dL 1 hour after taking the glucose and less than 140 mg per dL after2 hours. If after 2 hours the value is between 140 and 200 mg, this isregarded as abnormal glucose tolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference 85 cm in men and 90 cm in women;    -   2. Triglycerides: 150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≥130/85 mm Hg (SBP ≥130 or DBP ≥85)    -   5. Fasting blood glucose ≥110 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The term “SGLT2 inhibitor” in the scope of the present invention relatesto compounds, in particular to glucopyranosyl-derivatives, i.e.compounds having a glucopyranosyl-moiety, which show an inhibitoryeffect on the sodium-glucose transporter 2 (SGLT2), in particular thehuman SGLT2. The inhibitory effect on hSGLT2 measured as IC50 ispreferably below 1000 nM, even more preferably below 100 nM, mostpreferably below 50 nM. The inhibitory effect on hSGLT2 can bedetermined by methods known in the literature, in particular asdescribed in the application WO 2005/092877 or WO 2007/093610 (pages23/24), which are incorporated herein by reference in its entirety. Theterm “SGLT2 inhibitor” also comprises any pharmaceutically acceptablesalts thereof, hydrates and solvates thereof, including the respectivecrystalline forms.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the before mentioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of

Medicines and Health Care, 2000-2009).

DETAILED DESCRIPTION

The aspects according to the present invention, in particular thepharmaceutical compositions, methods and uses, refer to SGLT2 inhibitorsas defined hereinbefore and hereinafter.

Preferably the SGLT2 inhibitor is selected from aglucopyranosyl-substituted benzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugof one of the beforementioned SGLT2 inhibitors.

Compounds of the formula (I) and methods of their synthesis aredescribed for example in the following patent applications: WO2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO2008/055870.

In the above glucopyranosyl-substituted benzene derivatives of theformula (I) the following definitions of the substituents are preferred.

Preferably R¹ denotes chloro or cyano; in particular chloro.

Preferably R² denotes H.

Preferably R³ denotes ethyl, cyclopropyl, ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even morepreferably R³ denotes cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxyor (S)-tetrahydrofuran-3-yloxy. Most preferably R³ denotes ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

Preferred glucopyranosyl-substituted benzene derivatives of the formula(I) are selected from the group of compounds (I.1) to (I.11):

Even more preferred glucopyranosyl-substituted benzene derivatives ofthe formula (I) are selected from the compounds (I.6), (I.7), (I.8),(I.9) and (I.11).

Even more preferred glucopyranosyl-substituted benzene derivatives ofthe formula (I) are selected from the compounds (I.8) and (I.9).

According to this invention, it is to be understood that the definitionsof the above listed glucopyranosyl-substituted benzene derivatives ofthe formula (I) also comprise their hydrates, solvates and polymorphicforms thereof, and prodrugs thereof. With regard to the preferredcompound (I.7) an advantageous crystalline form is described in theinternational patent application WO 2007/028814 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.8), an advantageous crystalline form is described in theinternational patent application WO 2006/117360 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.9) an advantageous crystalline form is described in theinternational patent application WO 2006/117359 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.11) an advantageous crystalline form is described in theinternational patent application WO 2008/049923 which hereby isincorporated herein in its entirety. These crystalline forms possessgood solubility properties which enable a good bioavailability of theSGLT2 inhibitor. Furthermore, the crystalline forms arephysico-chemically stable and thus provide a good shelf-life stabilityof the pharmaceutical composition.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above in connection with the specified SGLT2 inhibitorsis specifically incorporated herein by reference in its entirety.

A preferred crystalline form (I.9X) of the compound (I.9) can becharacterized by an X-ray powder diffraction pattern that comprisespeaks at 18.84, 20.36 and 25.21 degrees 2Θ (±0.1 degrees 2Θ), whereinsaid X-ray powder diffraction pattern (XRPD) is made using CuK_(α1)radiation.

In particular said X-ray powder diffraction pattern comprises peaks at14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (±0.1 degrees2Θ), wherein said X-ray powder diffraction pattern is made usingCuK_(α1) radiation.

In particular said X-ray powder diffraction pattern comprises peaks at14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81,25.21 and 25.65 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powderdiffraction pattern is made using CuK_(α1) radiation.

More specifically, the crystalline form (I.9X) is characterised by anX-ray powder diffraction pattern, made using CuK_(α1) radiation, whichcomprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as contained in Table 1.

TABLE 1 X-ray powder diffraction pattern of the crystalline form (I.9X)(only peaks up to 30° in 2 Θ are listed): 2 Θ d-value Intensity I/I₀ [°][Å] [%] 4.46 19.80 8 9.83 8.99 4 11.68 7.57 4 13.35 6.63 14 14.69 6.0342 15.73 5.63 16 16.20 5.47 8 17.95 4.94 30 18.31 4.84 22 18.43 4.81 2318.84 4.71 100 19.16 4.63 42 19.50 4.55 31 20.36 4.36 74 20.55 4.32 1321.18 4.19 11 21.46 4.14 13 22.09 4.02 19 22.22 4.00 4 22.71 3.91 2823.44 3.79 27 23.72 3.75 3 24.09 3.69 3 24.33 3.66 7 24.81 3.59 24 25.213.53 46 25.65 3.47 23 26.40 3.37 2 26.85 3.32 8 27.26 3.27 17 27.89 3.202 28.24 3.16 3 29.01 3.08 4 29.41 3.03 18

Even more specifically, the crystalline form (I.9X) is characterised byan X-ray powder diffraction pattern, made using CuK_(α1) radiation,which comprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as shown in FIG. 1of WO 2006/117359.

Furthermore the crystalline form (I.9X) is characterised by a meltingpoint of about 151° C.±5° C. (determined via DSC; evaluated asonset-temperature; heating rate 10 K/min).The obtained DSC curve isshown in FIG. 2 of WO 2006/117359.

The X-ray powder diffraction patterns are recorded, within the scope ofthe present invention, using a STOE-STADI P-diffractometer intransmission mode fitted with a location-sensitive detector □(OED) and aCu-anode as X-ray source (CuKα1 radiation, □λ=1,54056 Å, 40 kV, 40 mA).In the Table 1 above the values “2Θ [°]” denote the angle of diffractionin degrees and the values “d [Å]” denote the specified distances in Åbetween the lattice planes. The intensity shown in the FIG. 1 of WO2006/117359 is given in units of cps (counts per second).

In order to allow for experimental error, the above described 2Θ valuesshould be considered accurate to ±0.1 degrees 2Θ, in particular ±0.05degrees 2Θ. That is to say, when assessing whether a given sample ofcrystals of the compound (I.9) is the crystalline form in accordancewith the invention, a 2Θ value which is experimentally observed for thesample should be considered identical with a characteristic valuedescribed above if it falls within ±0.1 degrees 2Θ of the characteristicvalue, in particular if it falls within ±0.05 degrees 2Θ of thecharacteristic value.

The melting point is determined by DSC (Differential ScanningCalorimetry) using a DSC 821 (Mettler Toledo).

In one embodiment, a pharmaceutical composition or dosage form accordingto the present invention comprises the compound (I.9), wherein at least50% by weight of the compound (I.9) is in the form of its crystallineform (I.9X) as defined hereinbefore. Preferably in said composition ordosage form at least 80% by weight, more preferably at least 90% byweight of the compound (I.9) is in the form of its crystalline form(I.9X) as defined hereinbefore.

The preferred dosage range of the SGLT2 inhibitor is in the range from0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferablyfrom 1 to 50 mg per day. The oral administration is preferred.Therefore, a pharmaceutical composition of the present invention maycomprise the hereinbefore mentioned amounts, in particular from 0.5 to50 mg, preferably 1 to 25 mg, even more preferably 2.5 to 12.5 mg.Particular dosage strengths for use in the present invention (e.g. pertablet or capsule) are for example 0.5, 1, 1.25, 2, 2.5, 5, 7.5, 10,12.5, 15, 20, 25 or 50 mg of the SGLT2 inhibitor, for example a compoundof the formula (I), in particular of the compound (I.9) or itscrystalline form (I.9X). Particularly preferred dosage strengths (e.g.per tablet or capsule) are for example 0.5, 1, 1.25, 2.5, 5, 10, or12.5, mg of the SGLT2 inhibitor, for example a compound of the formula(I), in particular of the compound (I.9) or its crystalline form (I.9X).

In one aspect, partner drugs to be combined with the SGLT-2 within thepharmaceutical compositions according to this invention are biguanides(e.g. metformin such as metformin hydrochloride).

A preferred partner drug within the meaning of this invention ismetformin, particularly metformin hydrochloride (1,1-dimethylbiguanidehydrochloride or metformin HCl).

The biguanide antihyperglycemic agent metformin is disclosed in U.S.Pat. No. 3,174,901.The preparation of metformin (dimethyldiguanide) andits hydrochloride salt is state of the art and was disclosed first byEmil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Otherpharmaceutically acceptable salts of metformin can be found in U.S.application Ser. No. 09/262,526 filed Mar. 4, 1999 or U.S. Pat. No.3,174,901. It is preferred that the metformin employed herein be themetformin hydrochloride salt.

Metformin is usually given in doses varying from about 250 mg to 3000mg, particularly from 500 mg to 2000 mg up to 2500 mg per day usingvarious dosage regimens.

A dosage range of the partner drug metformin is usually from 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or from 300 mg to 1000 mgonce or twice a day.

The unit dosage strengths of the metformin hydrochloride for use in thepresent invention may be from 100 mg to 2000 mg or from 100 mg to 1500mg, preferably from 250 mg to 1000 mg. Particular dosage strengths maybe 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. Theseunit dosage strengths of metformin hydrochloride represent the dosagestrengths approved in the US for marketing to treat type 2 diabetes.More particular unit dosage strengths of metformin hydrochloride forincorporation into the fixed dose combination pharmaceuticalcompositions of the present invention are 500, 850 and 1000 mg ofmetformin hydrochloride.

In a further aspect of the present invention, the present inventionprovides a pharmaceutical composition, formulation, blend or dosage formof this invention which is substantially free of or only marginallycomprises impurities and/or degradation products; that means, forexample, that the composition, formulation, blend or dosage fromincludes about <5%, or about <4%, or about <3%, or less than about 2%,preferably less than about 1%, more preferably less than about 0.5%,even more preferably less than about 0.2% of any individual or totalimpurity or degradation product(s) by total weight.

Dosage Forms for the FDC Formulations of this Invention:

Another purpose of this invention is to develop the FDC formulations ofthis invention with a reasonable tablet size, with good tabletproperties (e.g. stability, hardness, friability, disintegration,dissolution profile, content uniformity and the like).

Thus, it has been found that suitable dosage forms for the FDCformulations of this invention are film-coated tablets (film-coating fordrug loading, such as particularly SGLT-2 inhibitor drug loading by filmcoating on tablet cores containing the partner drug), mono-layertablets, bi-layer tablets, tri-layer tablets and press-coated tablets(e.g. tablet-in-tablet or bull's eye tablet with SGLT-2 inhibitor core),which dosage forms are good measures to achieve the goal underconsideration of desired pharmaceutical profiles and characteristics ofa SGLT-2 inhibitor and a partner drug used.

Said dosage forms have been found to be applicable to the FDCformulations either keeping the original dissolution profiles of eachmono tablet or adjusting the profiles to desired levels, and areasonable tablet size.

A typical mono-layer tablet of this invention comprises a SGLT-2inhibitor, metformin hydrochloride, one or more fillers (such as e.g.corn starch), one or more binders (such as e.g. copovidone), one or moreglidants (such as e.g. colloidal anhydrous silica) and one or morelubricants (such as e.g. magnesium stearate).

In one embodiment of the present invention, the present invention isdirected to an oral solid pharmaceutical composition, preferably atablet, particularly a mono-layer tablet, wherein one or more of thefollowing applies:

-   -   the percentage of metformin hydrochloride is about 84% by weight        of total tablet core,    -   the percentage of SGLT-2 inhibitor is about 0.1%-2.12%, e.g.        0.1%-2.11% by weight of total tablet core,    -   the tablet crushing strength is higher than or equal 100 N,    -   the tablet friability is lower than or equal 0.5%,    -   the tablet core weight is from about 560 to about 1180 mg, and    -   the tablet disintegration time is lower than or equal 15 min.

In one embodiment, the SGLT-2 inhibitor a compound of the formula (I),in particular of the compound (I.9) or its crystalline form (I.9X).

In a preferred embodiment of the present invention, the presentinvention is directed to an oral solid pharmaceutical composition,preferably a tablet, particularly a mono-layer tablet comprising or madefrom

a compound of the formula (I), for example of the formula (I.9) or itscrystalline form (I.9X), e.g. in an amount of 0.5, 1, 1.25, 2.5, 5, 10or 12.5 mg,

metformin, particularly metformin hydrochloride, e.g. in an amount of500 mg, 850 mg or 1000 mg,

and one or more pharmaceutical excipients, particularly one or morefillers (e.g. corn starch), one or more binders (e.g. copovidone), oneor more glidants (e.g. colloidal anhydrous silica) and/or one or morelubricants (e.g. magnesium stearate),

as well as, optionally, a film coat e.g. comprising one or morefilm-coating agents (e.g. hypromellose), one or more plasticizers (e.g.propylene glycol, polyethylene glycol or triethyl citrate), one or morepigments (e.g. titanium dioxide, iron oxide red/yellow/black or mixturethereof) and/or one or more glidants (e.g. talc).

In a further aspect of the present invention, the present inventionprovides methods of manufacturing of the compositions, formulations,blends or dosage forms of this invention, such as e.g. by using methodsknown to one skilled in the art and/or in a manner as described herein,for example they may be obtained by processes comprising using (e.g.mixing, combining, blending and/or composing) the components and/oringredients, or pre-mixtures thereof, mentioned hereinbefore andhereinafter, as well as the present invention further providescompositions, formulations, blends or dosage forms obtainable by thesemethods or processes and/or obtainable from the components, ingredients,pre-mixtures and/or mixtures mentioned hereinbefore and hereinafter.

A method of manufacturing a tablet of this invention comprisestabletting (e.g. compression) of one or more final blends in form ofgranules. Granules of the (final) blend(s) according to this inventionmay be prepared by methods well-known to one skilled in the art (e.g.high shear wet granulation or fluid bed granulation). Granules accordingto this invention as well as details of granulation processes (includingtheir separate steps) for the preparation of granules of this inventionare described by way of example in the following examples.

An illustrative granulation process for the preparation of granulescomprising the mono-layer composition comprises

i.) combining (e.g. dissolving or dispersing) a binder (e.g. copovidone)and, optionally, the SGLT-2 inhibitor (e.g. a compound of the formula(I), for example of the formula (I.9) or its crystalline form (I.9X)) ina solvent or mixture of solvents such as purified water at ambienttemperature to produce a granulation liquid;

ii.) blending metformin HCl, a filler (e.g. corn starch) and,optionally, the SGLT-2 inhibitor in a suitable mixer (e.g. fluid-bedgranulator) to produce a pre-mix;

wherein the SGLT-2 inhibitor may be included either in the granulationliquid obtained in i.) or in the pre-mix obtained in ii.), preferablythe SGLT-2 inhibitor is dispersed in the granulation liquid and isabsent in the pre-mix;

iii.) spraying the granulation-liquid into the pre-mix and granulatingthe mixture for example in a fluid-bed granulator, preferably under drycondition;

iv.) drying the granulate, e.g. at about 70° C. inlet air temperatureuntil the desired loss on drying value in the range of 1-3%, for example0.8-2%, is obtained;

v.) delumping the dried granulate for example by sieving through a sievewith a mesh size of 0.5 to 1.0 mm;

vi.) blending the sieved granulate and preferably sieved glidant (e.g.colloidal anhydrous silica) in a suitable blender;

vii.) adding preferably sieved lubricant (e.g. magnesium stearate) tothe granulate for final blending for example in the free-fall blender.

Preferentially, a mono-layer tablet according to this inventioncomprises or is obtainable from a mixture comprising the SGLT-2inhibitor and metformin.

A typical bi-layer tablet of this invention comprises

a SGLT-2 inhibitor portion comprising a SGLT-2 inhibitor, one or morefillers (such as e.g. D-mannitol, pregelatinized starch and cornstarch), one or more binders (such as e.g. copovidone) and one or morelubricants (such as e.g. magnesium stearate),

and

a metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

A typical press-coated tablet (tablet-in-tablet or bull's eye tablet) ofthis invention comprises a SGLT-2 inhibitor core portion comprising aSGLT-2 inhibitor, one or more fillers (such as e.g. D-mannitol,pregelatinized starch and corn starch), one or more binders (such ase.g. copovidone) and one or more lubricants (such as e.g. magnesiumstearate),

and

a metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

A typical film-coated tablet (the SGLT-2 inhibitor coating on metforminHCl tablet, i.e. drug layering by film-coating for drug loading) of thisinvention comprises

a metformin HCl core portion comprising metformin hydrochloride, one ormore fillers (such as e.g. corn starch), one or more binders (such ase.g. copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate),

wherein said core portion is seal-coated with a film coat comprising oneor more film-coating agents (such as e.g. hypromellose), one or moreplasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol6000, Macrogol 8000), one or more pigments (such as e.g. titaniumdioxide, iron oxide red/yellow/black or mixture thereof) and one or moreglidants (such as e.g. talc);

and

a SGLT-2 inhibitor layer comprising a SGLT-2 inhibitor, one or morefilm-coating agents (such as e.g. hypromellose) and one or moreplasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol6000, or Macrogol 8000, triethyl citrate).

Another typical film-coated tablet (the SGLT-2 inhibitor coating onmetformin HCl tablet, i.e. drug layering by film-coating for drugloading) of this invention comprises

a metformin HCl core portion comprising metformin hydrochloride, one ormore fillers (such as e.g. corn starch), one or more binders (such ase.g. copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate),

wherein said core portion is seal-coated with a film coat comprising oneor more film-coating agents (such as e.g. hypromellose), one or moreplasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol6000, or Macrogol 8000, triethyl citrate), one or more pigments (such ase.g. titanium dioxide, iron oxide red/yellow/black or mixture thereof)and one or more glidants (such as e.g. talc);

and

a SGLT-2 inhibitor layer comprising a SGLT-2 inhibitor, one or morefilm-coating agents (such as e.g. hypromellose) and one or moreplasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol6000, or Macrogol 8000, triethyl citrate).

Preferably, these abovementioned tablets (mono-, bi-layer, press-coatedand drug-coated tablets) are further over-coated with a final film coat,which comprises a film-coating agent (such as e.g. hypromellose), aplasticizer (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000,or Macrogol 8000, triethyl citrate), pigments (such as e.g. titaniumdioxide, iron oxide red/yellow/black or mixture thereof) and a glidant(such as e.g. talc). Typically this additional film over-coat mayrepresent 1-4%, preferentially 1-2%, of the total mass of thecomposition.

A pharmaceutical composition or dosage form according to the presentinvention may be an immediate release pharmaceutical composition ordosage form, or a time-release pharmaceutical composition or dosageform.

Pharmaceutical immediate release dosage forms of this inventionpreferably have dissolution properties such that after 45 minutes foreach of the active ingredients at least 75%, even more preferably atleast 90% by weight of the respective active ingredient is dissolved. Ina particular embodiment, after 30 minutes for each of the activeingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 70-75%(preferably at least 80%) by weight of the respective active ingredientis dissolved. In a further embodiment, after 15 minutes for each of theactive ingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 55-60%by weight of the respective active ingredient is dissolved. Thedissolution properties can be determined in standard dissolution tests,e.g. according to standard pharmacopeias (e.g. using paddle method withagitation speed of 50 or 75 or 100 rpm, dissolution medium pH 6.8 at atemperature of 37° C.).

A time-release dosage form refers to a formula that is not an immediaterelease dosage form. In a time-release dosage form the release of theactive ingredient is slow and occurs over time. Time-release dosageforms are also known as sustained-release (SR), sustained-action (SA),extended-release (ER, XR, or XL), time-release or timed-release,controlled-release (CR), modified release (MR), or continuous-release(CR or Contin), In one aspect, a time-release dosage form may be abi-layer tablet in which one or more of the active ingredients isreleased slowly. In one aspect, in a pharmaceutical composition andpharmaceutical dosage form according to the invention the SGLT-2inhibitor, for example a compound of the formula (I), for example of theformula (I.9) or its crystalline form (I.9X), or the partner drug, forexample a biguanide, for example metformin such as metforminhydrochloride, is time-release.

In another aspect, in a pharmaceutical composition and pharmaceuticaldosage form according to the invention the SGLT-2 inhibitor, for examplea compound of the formula (I), for example of the formula (I.9) or itscrystalline form (I.9X), and the partner drug, for example a biguanide,for example metformin such as metformin hydrochloride, are time-release.

In the pharmaceutical compositions and pharmaceutical dosage formsaccording to the invention the SGLT-2 inhibitor, for example a compoundof the formula (I), for example of the formula (I.9) or its crystallineform (I.9X), preferably has a particle size distribution (preferably byvolume) such that at least 90% of the respective active pharmaceuticalingredient has a particle size smaller than 200 μm, i.e. X90<200 μm,more preferably X90≤150 μm. More preferably the particle sizedistribution is such that X90≤100 μm, more preferably X90≤90 μm, evenmore preferably X90≤75 μm. In addition the particle size distribution ispreferably such that X90>1 μm, more preferably X90≥5 μm, most preferablyX90≥10 μm. Therefore preferred particle size distributions are such that1 μm<X90<200 μm, particularly 1 μm<X90≤150 μm, more preferably 5μm≤X90≤150 μm, even more preferably 5 μm≤X90≤100 μm, even morepreferably 10 μm≤X90≤100 μm. A preferred example of a particle sizedistribution of the SGLT-2 inhibitor is 20 μm≤X90≤50 μm. It can be foundthat a pharmaceutical composition comprising compound (I.9), orcrystalline form (I.9X) of compound (I.9) with a particle sizedistribution as indicated hereinbefore shows desired properties (e.g.with regard to dissolution, content uniformity, production, or thelike). The indicated particle size properties are determined bylaser-diffraction method, in particular low angle laser lightscattering, i.e. Fraunhofer diffraction. Alternatively, the particlesize properties can be also determined by microscopy (e.g. electronmicroscopy or scanning electron microscopy). The results of the particlesize distribution determined by different techniques can be correlatedwith one another.

Optimized Formulation of Metformin HCl Portion:

Another purpose of this invention is to provide improved formulations ofthe metformin HCl portion of the pharmaceutical compositions accordingto this invention.

For the metformin HCl part a high drug load is advantageous to beachieved as a pre-requisite for a reasonable small tablet size.

Thus, it has been found that drug load of metformin HCl andcompactability (compression force-crushing strength profile) of thetablets of this invention can be improved by surface treatment ofmetformin HCl with a water-soluble polymer, particularly copolyvidone.

Several water-soluble polymers including polyvinyl alcohol (PVA),hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose(MC), Povidone (PVP) and copolyvidone may be tested to improvecompactability (compression force-crushing strength profile). As theresults, PVA shows the best effect in terms of compactability but themanufacturability can be poor due to sticking problem during fluid-bedgranulation. Further on, PVA may be not finally selected because of itsnegative impact on the stability of certain SGLT-2 inhibitors of thisinvention.

Formulation optimization studies have identified a composition with over83% drug load of metformin HCl and improved crushing strength bysurface-treatment of metformin HCl with the water-soluble polymercopolyvidone.

Therefore, finally, copolyvidone is selected and advantageouslyresulting in stable formulations and the viscosity of the granulatingsolution is enough low to prepare the aqueous solution and operatespraying by a fluid-bed granulator.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the pharmaceutical composition may also be used accordingly inveterinary medicine in mammals. In the scope of this invention adultpatients are preferably humans of the age of 18 years or older.

As described hereinbefore by the administration of the pharmaceuticalcomposition according to this invention and in particular in view of thehigh SGLT2 inhibitory activity of the SGLT2 inhibitors therein,excessive blood glucose is excreted through the urine of the patient, sothat no gain in weight or even a reduction in body weight may result.Therefore, a treatment or prophylaxis according to this invention isadvantageously suitable in those patients in need of such treatment orprophylaxis who are diagnosed of one or more of the conditions selectedfrom the group consisting of overweight and obesity, in particular classI obesity, class II obesity, class III obesity, visceral obesity andabdominal obesity. In addition a treatment or prophylaxis according tothis invention is advantageously suitable in those patients in which aweight increase is contraindicated. The pharmaceutical composition aswell as the methods according to the present invention allow a reductionof the HbA1c value to a desired target range, for example <7% andpreferably <6.5%, for a higher number of patients and for a longer timeof therapeutic treatment compared with a corresponding monotherapy or atherapy using only two of the combination partners.

The pharmaceutical composition according to this invention and inparticular the SGLT2 inhibitor therein exhibits a very good efficacywith regard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

Furthermore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   -   (a) a fasting blood glucose or serum glucose concentration        greater than 110 mg/dL, in particular greater than 125 mg/dL;    -   (b) a postprandial plasma glucose equal to or greater than 140        mg/dL;    -   (c) an HbA1c value equal to or greater than 6.5%, in particular        equal to or greater than 7.0%, especially equal to or greater        than 7.5%, even more particularly equal to or greater than 8.0%.

The present invention also discloses the use of the pharmaceuticalcomposition for improving glycemic control in patients having type 2diabetes or showing first signs of pre-diabetes. Thus, the inventionalso includes diabetes prevention. If therefore a pharmaceuticalcomposition according to this invention is used to improve the glycemiccontrol as soon as one of the above-mentioned signs of pre-diabetes ispresent, the onset of manifest type 2 diabetes mellitus can be delayedor prevented.

Furthermore, the pharmaceutical composition according to this inventionis particularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present invention,there is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof whois diagnosed with impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG) with insulin resistance, with metabolic syndromeand/or with type 2 or type 1 diabetes mellitus characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

According to another preferred embodiment of the present invention,there is provided a method for improving gycemic control in patients, inparticular in adult patients, with type 2 diabetes mellitus as anadjunct to diet and exercise.

Therefore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   -   (a) insufficient glycemic control with diet and exercise alone;    -   (b) insufficient glycemic control despite oral monotherapy with        metformin, in particular despite oral monotherapy at a maximal        tolerated dose of metformin;    -   (c) insufficient glycemic control despite oral monotherapy with        another antidiabetic agent, in particular despite oral        monotherapy at a maximal tolerated dose of the other        antidiabetic agent.

The lowering of the blood glucose level by the administration of anSGLT2 inhibitor according to this invention is insulin-independent.Therefore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   -   (a) obesity (including class I, II and/or III obesity), visceral        obesity and/or abdominal obesity,    -   (b) triglyceride blood level ≥150 mg/dL,    -   (c) HDL-cholesterol blood level <40 mg/dL in female patients and        <50 mg/dL in male patients,    -   (d) a systolic blood pressure ≥130 mm Hg and a diastolic blood        pressure ≥85 mm Hg,    -   (e) a fasting blood glucose level ≥110 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance(IGT), impaired fasting blood glucose (IFG), with insulin resistanceand/or with metabolic syndrome suffer from an increased risk ofdeveloping a cardiovascular disease, such as for example myocardialinfarction, coronary heart disease, heart insufficiency, thromboembolicevents. A glycemic control according to this invention may result in areduction of the cardiovascular risks.

A pharmaceutical composition according to this invention exhibits a goodsafety profile. Therefore, a treatment or prophylaxis according to thisinvention is advantageously possible in those patients for which themono-therapy with another antidiabetic drug, such as for examplemetformin, is contraindicated and/or who have an intolerance againstsuch drugs at therapeutic doses. In particular, a treatment orprophylaxis according to this invention may be advantageously possiblein those patients showing or having an increased risk for one or more ofthe following disorders: renal insufficiency or diseases, cardiacdiseases, cardiac failure, hepatic diseases, pulmonal diseases,catabolytic states and/or danger of lactate acidosis, or female patientsbeing pregnant or during lactation.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

A pharmaceutical composition according to this invention is particularlysuitable in the long term treatment or prophylaxis of the diseasesand/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present inventionprovides a method for therapy, preferably oral therapy, for improvement,especially long term improvement, of glycemic control in patients withtype 2 diabetes mellitus, especially in patients with late stage type 2diabetes mellitus, in particular in patients additionally diagnosed ofoverweight, obesity (including class I, class II and/or class IIIobesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of the pharmaceutical compositionaccording to this invention to be administered to the patient andrequired for use in treatment or prophylaxis according to the presentinvention will vary with the route of administration, the nature andseverity of the condition for which treatment or prophylaxis isrequired, the age, weight and condition of the patient, concomitantmedication and will be ultimately at the discretion of the attendantphysician. In general, however, the SGLT2 inhibitor and partner drugaccording to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that by itsadministration the glycemic control in the patient to be treated isimproved.

In the following preferred ranges of the amount of the SGLT2 inhibitorand partner drug to be employed in the pharmaceutical composition andthe methods and uses according to this invention are described. Theseranges refer to the amounts to be administered per day with respect toan adult patient, in particular to a human being, for example ofapproximately 70 kg body weight, and can be adapted accordingly withregard to an administration 2, 3, 4 or more times daily and with regardto other routes of administration and with regard to the age of thepatient.

Within the scope of the present invention, the pharmaceuticalcomposition is preferably administered orally. Other forms ofadministration are possible and described hereinafter. Preferably theone or more dosage forms comprising the SGLT2 inhibitor and partner drugare oral or usually well known.

A pharmaceutical composition which is present as a separate or multipledosage form, preferably as a kit of parts, is useful in combinationtherapy to flexibly suit the individual therapeutic needs of thepatient.

According to a first embodiment a preferred kit of parts comprises acontainment containing a dosage form comprising the SGLT2 inhibitor andpartner drug and at least one pharmaceutically acceptable carrier.

A further aspect of the present invention is a manufacture comprisingthe pharmaceutical composition being present as separate dosage formsaccording to the present invention and a label or package insertcomprising instructions that the separate dosage forms are to beadministered in combination or alternation.

According to a first embodiment a manufacture comprises (a) apharmaceutical composition according to the present invention and (b) alabel or package insert which comprises instructions that the medicamentis to be administered.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a once daily or as divideddose administered at appropriate intervals, for example as two, three ormore doses per day.

The pharmaceutical composition may be formulated for oral, rectal,nasal, topical (including buccal and sublingual), transdermal, vaginalor parenteral (including intramuscular, sub-cutaneous and intravenous)administration in liquid or solid form or in a form suitable foradministration by inhalation or insufflation. Oral administration ispreferred. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods include the stepof bringing into association the active ingredient with one or morepharmaceutically acceptable carriers, like liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, oral solutions, syrups, dry syrups, chewable tablets, troches,effervescent tablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc.

The pharmaceutical composition and the dosage forms preferably comprisesone or more pharmaceutical acceptable carriers which must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution, a suspension or as an emulsion, for example as syrups,elixirs or self-emulsifying delivery systems (SEDDS). The activeingredients may also be presented as a bolus, electuary or paste.Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, fillers, lubricants, disintegrants,or wetting agents. The tablets may be coated according to methods wellknown in the art. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups orelixirs, or may be presented as a dry product for constitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

The pharmaceutical composition according to the invention may also beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredients may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound(s) with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc.

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture are described in the WO 2006/120208 and WO 2007/031548.With regard to compound (I.9) an advantageous crystalline form isdescribed in the international patent application WO 2006/117359 whichhereby is incorporated herein in its entirety.

The active ingredients may be present in the form of a pharmaceuticallyacceptable salt. Pharmaceutically acceptable salts include, withoutbeing restricted thereto, such as salts of inorganic acid likehydrochloric acid, sulfuric acid and phosphoric acid; salts of organiccarboxylic acid like oxalic acid, acetic acid, citric acid, malic acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acidand glutamic acid and salts of organic sulfonic acid likemethanesulfonic acid and p-toluenesulfonic acid. The salts can be formedby combining the compound and an acid in the appropriate amount andratio in a solvent and decomposer. They can be also obtained by thecation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof maybe present in the form of a solvate such as a hydrate or alcohol adduct.

Any of the above mentioned pharmaceutical compositions and methodswithin the scope of the invention may be tested by animal models knownin the art. In the following, in vivo experiments are described whichare suitable to evaluate pharmacologically relevant properties ofpharmaceutical compositions and methods according to this invention.

Pharmaceutical compositions and methods according to this invention canbe tested in genetically hyperinsulinemic or diabetic animals like db/dbmice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty(ZDF) rats. In addition, they can be tested in animals withexperimentally induced diabetes like HanWistar or Sprague Dawley ratspretreated with streptozotocin.

The effect on glycemic control according to this invention can be testedafter single dosing in an oral glucose tolerance test in the animalmodels described hereinbefore. The time course of blood glucose isfollowed after an oral glucose challenge in overnight fasted animals.The pharmaceutical compositions according to the present inventionsignificantly improve glucose excursion, for example compared to anothermonotherapy, as measured by reduction of peak glucose concentrations orreduction of glucose AUC. In addition, after multiple dosing in theanimal models described hereinbefore, the effect on glycemic control canbe determined by measuring the HbA1c value in blood. The pharmaceuticalcompositions according to this invention significantly reduce HbA1c, forexample compared to another monotherapy or compared to adual-combination therapy.

The improved independence from insulin of the treatment according tothis invention can be shown after single dosing in oral glucosetolerance tests in the animal models described hereinbefore. The timecourse of plasma insulin is followed after a glucose challenge inovernight fasted animals.

The increase in active GLP-1 levels by treatment according to thisinvention after single or multiple dosing can be determined by measuringthose levels in the plasma of animal models described hereinbefore ineither the fasting or postprandial state. Likewise, a reduction inglucagon levels in plasma can be measured under the same conditions.

The effect of a SGLT2 inhibitor and partner drug according to thepresent invention on beta-cell regeneration and neogenesis can bedetermined after multiple dosing in the animal models describedhereinbefore by measuring the increase in pancreatic insulin content, orby measuring increased beta-cell mass by morphometric analysis afterimmunhistochemical staining of pancreatic sections, or by measuringincreased glucose-stimulated insulin secretion in isolated pancreaticislets.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES

1. Mono-Layer Tablet

Examples of the composition of mono-layer tablets for a SGLT-2 inhibitorof this invention (compound (I.9), or a crystalline form (I.9X) ofcompound (I.9))+metformin HCl FDC (Film-coated Tablets) is shown inTables I.1 to I.11.

TABLE 1.1 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 12.5/500 12.5/850 12.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%]Compound (I.9), or crystalline 12.50 2.11 12.50 1.25 12.50 1.06 form(I.9X) of compound (I.9) Metformin Hydrochloride 500.0 84.76 850.0 85.01000.0 84.75 Corn starch 22.63 3.83 44.5 4.45 57.7 4.89 Copovidone 47.28.0 80.0 8.0 94.4 8.0 Colloidal Anhydrous Silica 2.95 0.5 5.0 0.5 5.90.5 Magnesium stearate 4.72 0.8 8.0 0.8 9.44 0.80 Total Mass (tabletcore) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose 2910 6.0050.00 8.00 50.00 9.00 50.00 Propylene glycol 0.60 5.00 0.80 5.00 0.905.00 Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.76 23.003.68 24.00 4.14 24.00 Iron oxide, black 0.12 1.00 0.16 1.00 0.18 1.00Iron oxide, red 0.12 1.00 0.16 1.00 0.18 1.00 Total Mass (film-coat)12.00 100.00 16.00 100.00 18.00 100.00 Total Mass (coated tablet) 602.001016.00 1198.00

TABLE 1.2 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 12.5/500 12.5/850 12.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%]Compound (I.9), or crystalline 12.50 2.12 12.50 1.25 12.50 1.06 form(I.9X) of compound (I.9) Metformin Hydrochloride 500.0 84.75 850.0 85.01000.0 84.75 Corn starch 22.63 3.83 44.5 4.45 57.76 4.89 Copovidone 47.28.0 80.0 8.0 94.4 8.0 Colloidal Anhydrous Silica 2.95 0.5 5.0 0.5 5.90.5 Magnesium stearate 4.72 0.8 8.0 0.8 9.44 0.80 Total Mass (tabletcore) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose 2910 6.0050.00 8.00 50.00 9.00 50.00 Macrogol 400 0.60 5.00 0.80 5.00 0.90 5.00Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.928 24.40 3.74423.40 3.78 21.00 Iron oxide, black 0.036 0.30 0.128 0.80 0.36 2.00 Ironoxide, red 0.036 0.30 0.128 0.80 0.36 2.00 Total Mass (film-coat) 12.00100.00 16.00 100.00 18.00 100.00 Total Mass (coated tablet) 602.001016.00 1198.00

TABLE 1.3 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 5/500 5/850 5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] Compound(I.9), or crystalline 5.00 0.85 5.00 0.50 5.00 0.42 form (I.9X) ofcompound (I.9) Metformin Hydrochloride 500.0 84.76 850.00 85.00 1000.0084.75 Corn starch 30.13 5.09 52.00 5.20 65.26 5.53 Copovidone 47.20 8.0080.00 8.00 94.40 8.00 Colloidal Anhydrous Silica 2.95 0.50 5.00 0.505.90 0.50 Magnesium stearate 4.72 0.80 8.00 0.80 9.44 0.80 Total Mass(tablet core) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose2910 6.00 50.00 8.00 50.00 9.00 50.00 Propylene glycol 0.60 5.00 0.805.00 0.90 5.00 Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide2.76 23.00 3.68 24.00 4.14 24.00 Iron oxide, black 0.12 1.00 0.16 1.000.18 1.00 Iron oxide, red 0.12 1.00 0.16 1.00 0.18 1.00 Total Mass(film-coat) 12.00 100.00 16.00 100.00 18.00 100.00 Total Mass (coatedtablet) 602.00 1016.00 1198.00

TABLE 1.4 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 5/500 5/850 5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] Compound(I.9), or crystalline 5.00 0.85 5.00 0.50 5.00 0.42 form (I.9X) ofcompound (I.9) Metformin Hydrochloride 500.0 84.75 850.00 85.00 1000.0084.75 Corn starch 30.13 5.10 52.00 5.20 65.26 5.53 Copovidone 47.20 8.0080.00 8.00 94.40 8.00 Colloidal Anhydrous Silica 2.95 0.50 5.00 0.505.90 0.50 Magnesium stearate 4.72 0.80 8.00 0.80 9.44 0.80 Total Mass(tablet core) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose2910 6.00 50.00 8.00 50.00 9.00 50.00 Macrogol 400 0.60 5.00 0.80 5.000.90 5.00 Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.92824.40 3.744 23.40 3.78 21.00 Iron oxide, black 0.036 0.30 0.128 0.800.36 2.00 Iron oxide, red 0.036 0.30 0.128 0.80 0.36 2.00 Total Mass(film-coat) 12.00 100.00 16.00 100.00 18.00 100.00 Total Mass (coatedtablet) 602.00 1016.00 1198.00

TABLE 1.5 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 12.5/500 12.5/850 12.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%]Compound (I.9), or crystalline 12.50 2.12 12.50 1.25 12.50 1.06 form(I.9X) of compound (I.9) Metformin Hydrochloride 500.0 84.75 850.0 85.01000.0 84.75 Corn starch 22.63 3.83 44.5 4.45 57.76 4.89 Copovidone 47.28.0 80.0 8.0 94.4 8.0 Colloidal Anhydrous Silica 2.95 0.5 5.0 0.5 5.90.5 Magnesium stearate 4.72 0.8 8.0 0.8 9.44 0.80 Total Mass (tabletcore) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose 2910 6.0050.00 8.00 50.00 9.00 50.00 Macrogol 400 0.60 5.00 0.80 5.00 0.90 5.00Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.928 24.40 3.74423.40 3.78 21.00 Iron oxide, black 0.0012 0.10 0.08 0.50 0.36 2.00 Ironoxide, red 0.0012 0.10 0.08 0.50 0.36 2.00 Total Mass (film-coat) 12.00100.00 16.00 100.00 18.00 100.00 Total Mass (coated tablet) 602.001016.00 1198.00

TABLE 1.6 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg 5/500 5/850 5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] Compound(I.9), or crystalline 5.00 0.85 5.00 0.50 5.00 0.42 form (I.9X) ofcompound (I.9) Metformin Hydrochloride 500.0 84.75 850.00 85.00 1000.0084.75 Corn starch 30.13 5.10 52.00 5.20 65.26 5.53 Copovidone 47.20 8.0080.00 8.00 94.40 8.00 Colloidal Anhydrous Silica 2.95 0.50 5.00 0.505.90 0.50 Magnesium stearate 4.72 0.80 8.00 0.80 9.44 0.80 Total Mass(tablet core) 590.00 100.00 1000.00 100.00 1180.00 100.00 Hypromellose2910 6.00 50.00 8.00 50.00 9.00 50.00 Macrogol 400 0.60 5.00 0.80 5.000.90 5.00 Talc 2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.92824.40 3.744 23.40 3.78 21.00 Iron oxide, black 0.0012 0.10 0.08 0.500.36 2.00 Iron oxide, red 0.0012 0.10 0.08 0.50 0.36 2.00 Total Mass(film-coat) 12.00 100.00 16.00 100.00 18.00 100.00 Total Mass (coatedtablet) 602.00 1016.00 1198.00

TABLE 1.7 Examples of the composition of SGLT-2 inhibitor + MetforminHCl FDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metforminHCl), mg 1.25/500 1.25/850 1.25/1000 Ingredient [mg] [%] [mg] [%] [mg][%] Compound (I.9), or crystalline 1.25 0.21 1.25 0.125 1.25 0.10 form(I.9X) of compound (I.9) Metformin Hydrochloride 500.0 84.76 850.0085.00 1000.00 84.75 Corn starch 33.88 5.73 55.75 5.575 69.01 5.85Copovidone 47.20 8.00 80.00 8.00 94.40 8.00 Colloidal Anhydrous Silica2.95 0.50 5.00 0.50 5.90 0.50 Magnesium stearate 4.72 0.80 8.00 0.809.44 0.80 Total Mass (tablet core) 590.00 100.00 1000.00 100.00 1180.00100.00 Hypromellose 2910 6.00 50.00 8.00 50.00 9.00 50.00 Propyleneglycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc 2.40 20.00 3.20 20.00 3.6020.00 Titanium dioxide 2.76 23.00 3.68 24.00 4.14 24.00 Iron oxide,black 0.12 1.00 0.16 1.00 0.18 1.00 Iron oxide, red 0.12 1.00 0.16 1.000.18 1.00 Total Mass (film-coat) 12.00 100.00 16.00 100.00 18.00 100.00Total Mass (coated tablet) 602.00 1016.00 1198.00

TABLE 1.8 Examples of the composition of SGLT-2 inhibitor + MetforminHCl FDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metforminHCl), mg 1.25/500 1.25/850 1.25/1000 Ingredient [mg] [%] [mg] [%] [mg][%] Compound (I.9), or crystalline 1.25 0.21 1.25 0.125 1.25 0.10 form(I.9X) of compound (I.9) Metformin Hydrochloride 500.0 84.76 850.0085.00 1000.00 84.75 Corn starch 33.88 5.73 55.75 5.575 69.01 5.85Copovidone 47.20 8.00 80.00 8.00 94.40 8.00 Colloidal Anhydrous Silica2.95 0.50 5.00 0.50 5.90 0.50 Magnesium stearate 4.72 0.80 8.00 0.809.44 0.80 Total Mass (tablet core) 590.00 100.00 1000.00 100.00 1180.00100.00 Hypromellose 2910 6.00 50.00 8.00 50.00 9.00 50.00 Propyleneglycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc 2.40 20.00 3.20 20.00 3.6020.00 Titanium dioxide 2.52 21.00 3.36 21.00 3.78 21.00 Iron oxide,black 0.24 2.00 0.32 2.00 0.36 2.00 Iron oxide, red 0.24 2.00 0.32 2.000.36 2.00 Total Mass (film-coat) 12.00 100.00 16.00 100.00 18.00 100.00Total Mass (coated tablet) 602.00 1016.00 1198.00

TABLE 1.9 Examples of the composition of SGLT-2 inhibitor + MetforminHCl FDC Mono-layer Tablets with MCC Dose Strength (SGLT-2inhibitor/metformin HCl), mg 1.25/500 1.25/850 1.25/1000 Ingredient [mg][%] [mg] [%] [mg] [%] Compound (I.9), or crystalline 1.25 0.21 1.250.125 1.25 0.10 form (I.9X) of compound (I.9) Metformin Hydrochloride500.0 84.76 850.00 85.00 1000.00 84.75 Microcrystalline cellulose 33.885.73 55.75 5.575 69.01 5.85 Copovidone 47.20 8.00 80.00 8.00 94.40 8.00Colloidal Anhydrous Silica 2.95 0.50 5.00 0.50 5.90 0.50 Magnesiumstearate 4.72 0.80 8.00 0.80 9.44 0.80 Total Mass (tablet core) 590.00100.00 1000.00 100.00 1180.00 100.00 Hypromellose 2910 6.00 50.00 8.0050.00 9.00 50.00 Propylene glycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.76 23.00 3.68 23.004.14 23.00 Iron oxide, black 0.12 1.00 0.16 1.00 0.18 1.00 Iron oxide,red 0.12 1.00 0.16 1.00 0.18 1.00 Total Mass (film-coat) 12.00 100.0016.00 100.00 18.00 100.00 Total Mass (coated tablet) 602.00 1016.001198.00

TABLE 1.10 Examples of the composition of SGLT-2 inhibitor + MetforminHCl FDC Mono-layer Tablets with MCC Dose Strength (SGLT-2inhibitor/metformin HCl), mg 12.5/500 12.5/850 12.5/1000 Ingredient [mg][%] [mg] [%] [mg] [%] Compound (I.9), or crystalline 12.50 2.11 12.501.25 12.50 1.06 form (I.9X) of compound (I.9) Metformin Hydrochloride500.0 84.76 850.00 85.00 1000.00 84.75 Microcrystalline cellulose 22.633.83 44.50 4.45 57.70 4.89 Copovidone 47.20 8.00 80.00 8.00 94.40 8.00Colloidal Anhydrous Silica 2.95 0.50 5.00 0.50 5.90 0.50 Magnesiumstearate 4.72 0.80 8.00 0.80 9.44 0.80 Total Mass (tablet core) 590.00100.00 1000.00 100.00 1180.00 100.00 Hypromellose 2910 6.00 50.00 8.0050.00 9.00 50.00 Propylene glycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc2.40 20.00 3.20 20.00 3.60 20.00 Titanium dioxide 2.76 23.00 3.68 23.004.14 23.00 Iron oxide, black 0.12 1.00 0.16 1.00 0.18 1.00 Iron oxide,red 0.12 1.00 0.16 1.00 0.18 1.00 Total Mass (film-coat) 12.00 100.0016.00 100.00 18.00 100.00 Total Mass (coated tablet) 602.00 1016.001198.00

TABLE 1.11 Examples of composition of SGLT-2 inhibitor + Metformin HClFDC Mono-layer Tablets Dose Strength (SGLT-2 inhibitor/metformin HCl),mg Material mg/tablet (Sum) Compound (I.9), or crystalline 5.000 mg5.000 mg 5.000 mg form (I.9X) of compound (I.9) Metformin HCl, milled500.000 mg  850.000 mg  1000.000 mg   Corn starch, undried 30.130 mg 54.721 mg  65.260 mg  Copovidone 47.200 mg  80.240 mg  94.400 mg  Water,purified * 175.000 mg  297.500 mg  350.000 mg  Colloidal AnhydrousSilica 2.950 mg 5.015 mg 5.900 mg Magnesium stearate 4.720 mg 8.024 mg9.440 mg Total (core) 590.000 mg  1003.000 mg   1180.000 mg  Hypromellose 2910 6.000 mg 8.500 mg 9.500 mg Macrogol 400 0.600 mg 0.850mg 0.950 mg Titanium dioxide 2.880 mg 4.216 mg 3.990 mg Talc 2.400 mg3.400 mg 3.800 mg Iron oxide, black 0.060 mg 0.017 mg 0.380 mg Ironoxide, red 0.060 mg 0.017 mg 0.380 mg Water, purified * 84.000 mg 119.000 mg  133.000 mg  Total (film coated tablet) 602.000 mg  1020.000mg   1199.000 mg   Name of colours: (or shift of pale grayish brownpinkish white dark grayish brown colours between dose strengths) to palegrayish ruby to dark grayish ruby Dose Strength (SGLT-2inhibitor/metformin HCl), mg Material mg/tablet (Sum) Compound (I.9), orcrystalline 12.500 mg  12.500 mg  12.500 mg  form (I.9X) of compound(I.9) Metformin HCl, milled 500.000 mg  850.000 mg  1000.000 mg   Cornstarch, undried 22.630 mg  47.221 mg  57.760 mg  Copovidone 47.200 mg 80.240 mg  94.400 mg  Water, purified * 175.000 mg  297.500 mg 350.000mg  Colloidal Anhydrous Silica 2.950 mg 5.015 mg 5.900 mg Magnesiumstearate 4.720 mg 8.024 mg 9.440 mg Total (core) 590.000 mg  1003.000mg   1180.000 mg   Hypromellose 2910 6.000 mg 8.500 mg 9.500 mg Macrogol400 0.600 mg 0.850 mg 0.950 mg Titanium dioxide 2.880 mg 4.216 mg 3.990mg Talc 2.400 mg 3.400 mg 3.800 mg Iron oxide, black 0.060 mg 0.017 mg0.380 mg Iron oxide, red 0.060 mg 0.017 mg 0.380 mg Water, purified *84.000 mg  119.000mg  133.000 mg  Total (film coated tablet) 602.000 mg 1020.000 mg   1199.000 mg   Name of colours: (or shift of pale grayishbrown pinkish white dark grayish brown colours between dose strengths)to pale grayish ruby to dark grayish ruby Dose Strength (SGLT-2inhibitor/metformin HCl), mg Material 5/500 5/850 5/1000 Compound (I.9),or crystalline 0.85% 0.50% 0.42% form (I.9X) of compound (I.9) MetforminHCl, milled 84.75% 84.75% 84.75% Corn starch, undried 5.11% 5.46% 5.53%Copovidone 8.00% 8.00% 8.00% Water, purified * Colloidal AnhydrousSilica 0.50% 0.50% 0.50% Magnesium stearate 0.80% 0.80% 0.80% Total(core) 100.00% 100.00% 100.00% Hypromellose 2910 50.00% 50.00% 50.00%Macrogol 400 5.00% 5.00% 5.00% Titanium dioxide 24.00% 24.80% 21.00%Talc 20.00% 20.00% 20.00% Iron oxide, black 0.50% 0.10% 2.00% Ironoxide, red 0.50% 0.10% 2.00% Water, purified * Total (film coatedtablet) 100.00% 100.00% 100.00% Dose Strength (SGLT-2inhibitor/metformin HCl), mg Material 12.5/500 12.5/850 12.5/1000Compound (I.9), or crystalline 2.12% 1.25% 1.06% form (I.9X) of compound(I.9) Metformin HCl, milled 84.75% 84.75% 84.75% Corn starch, undried3.84% 4.71% 4.89% Copovidone 8.00% 8.00% 8.00% Water, purified *Colloidal Anhydrous Silica 0.50% 0.50% 0.50% Magnesium stearate 0.80%0.80% 0.80% Total (core) 100.00% 100.00% 100.00% Hypromellose 291050.00% 50.00% 50.00% Macrogol 400 5.00% 5.00% 5.00% Titanium dioxide24.00% 24.80% 21.00% Talc 20.00% 20.00% 20.00% Iron oxide, black 0.50%0.10% 2.00% Iron oxide, red 0.50% 0.10% 2.00% Water, purified * Total(film coated tablet) 100.00% 100.00% 100.00% * Removed duringprocessing, does not appear in the final product.

A broad dose range of SGLT-2 inhibitor, e.g. 1.25, 5 or 12.5 mg, couldbe used, in which case the amount of binder corn starch ormicrocrystalline cellulose is adjusted. Instead of corn starch,microcrystalline cellulose could be used. In the further description ofthe manufacturing procedure only corn starch is described.

Manufacturing Procedure (Mono-Layer Tablets):

SGLT-2 inhibitor of this invention (e.g. compound (I.9), or crystallineform (I.9X) of compound (I.9))+metformin HCl FDC mono-layer tablets areproduced by a fluid-bed granulation process and a conventional tabletingprocess with a rotary press. Metformin HCl and corn starch, the SGLT-2inhibitor is either added as powder and premixed before fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64 and purified water, or directly dispersed inthe “granulation liquid”. Alternatively, the SGLT-2 inhibitor is addedas powder together with metformin-HCl and corn starch to the fluid bedgranulator. After finishing of fluid-bed granulation, the granulate issieved with a suitable screen. The sieved granulate is blended withcolloidal anhydrous silica (Aerosil 200) and magnesium stearate as alubricant. The final mixture is compressed into tablets using aconventional rotary tablet press.

The tablet cores may be film-coated by an aqueous film-coatingsuspension, containing hypromellose as film-forming agent, propyleneglycol as plasticizer, talc as glidant and the pigments black, red,yellow iron oxide and mixture of red/yellow/black and titanium dioxide.

Narrative more specific description of the preferred manufacturingprocess for the mono-layer tablets:

-   -   a) Metformin HCl and corn starch are sieved using a screen with        a mesh size of 0.5 to 1 mm before dispensing.    -   b) Compound (I.9), or crystalline form (I.9X) of compound (I.9))        and finally copolyvidon are dissolved resp. dispersed in        purified water at ambient temperature with a propeller mixer to        produce the “Granulation Liquid”.    -   c) Metformin HCl and corn starch are sucked into a chamber of a        suitable fluid-bed granulator and preheated up to a product        temperature target of approx. 36° C. Preheating is optionally.        Alternatively, the compound (I.9), or crystalline form (I.9X) of        compound (I.9)) and metformin-HCl and corn starch are sucked        into a chamber of suitable fluid-bed granulator.    -   d) Immediately after the product temperature target is reached,        the “Granulation Liquid” is sprayed into the mixture for        fluid-bed granulating under dry condition to avoid blocking        during granulation.    -   e) At the end of spraying, the resultant granulate is dried at        approx. 70 C inlet air temperature until the desired LOD value        (i.e. 1-3%, for example 0.8-2%) is reached.    -   f) The granulate is sieved using a screen with a mesh size of        0.5 to 1.0 mm.    -   g) The sieved granulate and colloidal anhydrous silica        (Aerosil 200) are blended with a suitable blender. Aerosil 200        should be pre-sieved with a small portion of the sieved        granulate through a 0.8 mm-screen before use.    -   h) Magnesium stearate is passed through a 0.8 mm sieve and added        into the granulate. Subsequently the “Final Blend” is produced        by final blending in the free-fall blender.    -   i) The “Final Blend” is compressed into tablets with a rotary        press.    -   j) Titanium dioxide, polyethylene glycol or propylene glycol and        iron oxide (yellow, red, black or mixture thereof) are dispersed        in purified water with a high shear homo-mixer. Then,        hypromellose and talc are added and dispersed with a homo-mixer        and propeller mixer at ambient temperature to produce the        “Coating Suspension”.    -   k) The tablet cores are coated with the “Coating Suspension” to        the target weight gain to produce the “Film-coated Tablets”. The        “Coating Suspension” should be stirred again before use and kept        stirring slowly during the coating (spraying) process.

Narrative more specific description of an alternative manufacturingprocess for the mono-layer tablets:

-   -   a) Metformin HCl is sieved using a screen with a mesh size of        0.5 to 1 mm before weighing.    -   b) copolyvidon are dissolved in purified water at ambient        temperature with a propeller mixer to produce the “Granulation        Liquid”    -   c) is added into the container, then blended with metformin HCl        and corn starch in the fluid-bed granulator.    -   d) The “Granulation Liquid” is sprayed into the mixture for        fluid-bed granulating under dry condition to avoid blocking        during granulation.    -   e) At the end of spraying, the resultant granulate is dried at        70-80 ° C. until the desired LOD value (i.e. 1-3%, for example        0.8-2%), in case the LOD is more than 2%.    -   f) The granulate is sieved using a screen with a mesh size of        0.5 to 1.0 mm.    -   g) The sieved granulate and colloidal anhydrous silica        (Aerosil 200) are blended with a suitable blender. Aerosil 200        should be sieved with a 0.5 mm-screen before use.    -   h) Magnesium stearate passed through a 0.5 mm sieve and added        into the granulate. Subsequently the “Final Blend” is produced        by final blending in the blender.    -   i) The “Final Blend” is compressed into tablets with a rotary        press.    -   j) Hypromellose and polyethylene glycol or propylene glycol are        dissolved in purified water with a propeller mixer. Talc,        titanium dioxide, and iron oxide (yellow, red and/or black and        mixture thereof) are dispersed in purified water with a        homo-mixer. The suspension is added into the hypromellose        solution, then mixed with a propeller mixer at ambient        temperature to produce the “Coating Suspension”.    -   k) The tablet cores are coated with the “Coating Suspension” to        the target weight gain to produce the “Film-coated Tablets”. The        “Coating Suspension” should be stirred again before use and kept        stirring slowly during the coating (spraying) process.

2. Bi-Layer Tablet

Examples of the composition of bi-layer tablets for a SGLT-2 inhibitorof this invention (compound (I.9), or a crystalline form (I.9X) ofcompound (I.9))+metformin HCl FDC (Film-coated Tablets) is shown inTable 2.

TABLE 2 Examples of the composition of SGLT-2 inhibitor + Metformin HClBi-layer Tablets Dose Strength (SGLT-2 Dose Strength (SGLT-2inhibitor/metformin HCl), mg inhibitor/metformin HCl), mg 12.5/50012.5/850 12.5/1000 5/500 5/850 5/1000 Ingredient [mg] [mg] [mg] [mg][mg] [mg] SGLT-2 inhibitor-portion: (300) (300)  (400) (325) (325) (425) compound (I.9), or crystalline 12.50 12.50 12.50 5.00 5.00 5.00form (I.9X) of compound (I.9)) Lactose monohydrate 165.50 165.50 165.50181.25 181.25 181.25 Cellulose microcrystalline 125.00 125.00 125.00131.25 131.25 131.25 Hydroxypropylcellulose 3.00 3.00 3.00 3.75 3.753.75 Croscarmellose sodium 2.00 2.00 2.00 2.50 2.50 2.50 Colloidalsilicium dioxide 0.50 0.50 0.50 0.025 0.625 0.625 Magnesium stearate0.50 0.50 0.50 0.625 0.625 0.625 Metformin HCl-portion: (570) (969)(1140) (570) (969) (1140) Metformin Hydrochloride 500.0 850.00 1000.00500.0 850.00 1000.00 Corn starch 15.00 25.50 30.00 15.00 25.50 30.00Copovidone 47.50 80.57 95.00 47.50 80.57 95.00 Colloidal AnhydrousSilica 2.50 4.25 5.00 2.50 4.25 5.00 Magnesium stearate 5.00 8.50 10.005.00 8.50 10.00 Total Mass (tablet core) 870.0 1269.0 1540.0 895.01494.0 1565.0 Hypromellose 2910 7.00 9.00 10.00 7.00 9.00 10.00Propylene glycol 0.70 0.90 1.00 0.70 0.90 1.00 Talc 2.80 3.60 4.00 2.803.60 4.00 Titanium dioxide 3.22 4.14 4.60 3.22 4.14 4.60 Iron oxide,black 0.14 0.18 0.20 0.14 0.18 0.20 Iron oxide, red 0.14 0.18 0.20 0.140.18 0.20 Total Mass (film-coat) 14.00 18.000 20.000 14.00 18.000 20.000Total Mass (coated tablet) 684.00 1087.00 1260.00 709.00 1112.00 1285.00

A broad dose range of SGLT-2 inhibitor, eg. 1.25, 5 or 12.5 mg, could beused, in which case the amount of binder corn starch or microcrystallinecellulose is adjusted. Instead of corn starch, microcrystallinecellulose could be used. In the further description of the manufacturingprocedure only corn starch is described.

Manufacturing Procedure (Bi-Layer Tablets):

SGLT-2 inhibitor of this invention (e.g. compound (I.9), or crystallineform (I.9X) of compound (I.9))+metformin HCl FDC bi-layer tablets areproduced by a high-shear wet granulation process (for SGLT-2inhibitor-granulate), a fluid-bed granulation process (for metforminHCl-granulate), and bi-layer tableting process with a multi-layer rotarypress.

SGLT-2 inhibitor-granulate: By using a high-shear granulator the activeSGLT-2 inhibitor. The overall manufacturing process consisted offollowing steps:

1) Screen hydroxpropyl cellulose (HPC)

2) Add the intra-granular microcrystalline cellulose portion. SGLT-2inhibitor, lactose, HPC and croscarmelose sodium to the granulator

3) Granulate the blend with water.

4) Dry the granulate in Fluid bed drier: less than 1.5% LOD

5) Mill the granulation into the blender container

-   -   Quadro mill    -   Quadro mill screen—18 mesh.

6) Screen the following onto milled granulation in the container of atumble blender

-   -   Premix of the colloidal silicon dioxide with a portion of the        extra-granular microcrystalline cellulose screened through 20-25        mesh.    -   Remainder of the extra-granular microcrystalline cellulose and        blend.

7) Premix the magnesium stearate with a portion of the blendedgranulation, screen (18 mesh) onto the remainder of the granulation inthe blender.

Subsequently the “Final Blend A” is produced by final blending in asuitable blender.

Metformin HCl-granulate: Metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. Alternatively, theSGLT-2 inhibitor is added as powder together with metformin-HCl and cornstarch to the fluid bed granulator. After finishing of fluid-bedgranulation, the granulate is sieved with a suitable screen. The sievedgranulate is blended with colloidal anhydrous silica (Aerosil 200) andmagnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

-   -   a) Metformin HCl is sieved using a screen with a mesh size of        0.5 to 1 mm before weighing.    -   b) Copolyvidon is dissolved in purified water at ambient        temperature with a propeller mixer to produce the “Granulation        Liquid”    -   c) The “Granulation Liquid” is sprayed into the mixture for        fluid-bed granulating under dry condition to avoid blocking        during granulation.    -   d) At the end of spraying, the resultant granulate is dried at        70-80 ° C. until the desired LOD value (i.e. 0.8-2%, for example        1-2%), in case the LOD is more than 2%.    -   e) The granulate is sieved using a screen with a mesh size of        0.5 to 1.0 mm.    -   f) The sieved granulate and colloidal anhydrous silica        (Aerosil 200) are blended with a suitable blender. Aerosil 200        should be sieved with a 0.5 mm-screen before use.    -   g) Magnesium stearate passed through a 0.5 mm sieve and added        into the granulate. Subsequently the “Final Blend B” is produced        by final blending in the blender.

The “Final Blend A” and “Final Blend B” are compressed into bi-layertablets using a multi-layer rotary press. The tablet cores may befilm-coated by an aqueous film-coating suspension, containinghypromellose as film-forming agent, polyethylene glycol or propyleneglycol as plasticizer, talc as glidant and the pigments yellow, red,black iron oxide and mixture thereof and titanium dioxide.

Narrative more specific description of the manufacturing process for thefilm-coating:

-   -   a) Hypromellose and polyethylene glycol or propylene glycol are        dissolved in purified water with a propeller mixer. Talc,        titanium dioxide, and iron oxide (yellow, red or yellow and red)        are dispersed in purified water with a homo-mixer. The        suspension is added into the hypromellose solution, then mixed        with a propeller mixer at ambient temperature to produce the        “Coating Suspension”.    -   b) The tablet cores are coated with the “Coating Suspension” to        the target weight gain to produce the “Film-coated Tablets”. The        “Coating Suspension” should be stirred again before use and kept        stirring slowly during the coating (spraying) process.

3. Tablet-in-Tablet or Bull's Eye Tablet

Examples of the composition of Tablet-in-Tablet or Bull's eye tabletsfor a SGLT-2 inhibitor of this invention (compound (I.9), or crystallineform (I.9X) of compound (I.9))+metformin HCl FDC (Film-coated Tablets)is shown in Table 3.

TABLE 3 Examples of the composition of compound (I.9), or crystallineform (I.9X) of compound (I.9)) + Metformin HCl FDC Tablet-in-Tablet orBull's Eye Tablets Dose Strength (SGLT-2 Dose Strength (SGLT-2inhibitor/metformin HCl), mg inhibitor/metformin HCl), mg 12.5/50012.5/850 12.5/1000 5/500 5/850 5/1000 Ingredient [mg] [mg] [mg] [mg][mg] [mg] SGLT-2 inhibitor-portion: (100) (100)  (100) (125) (125) (125) compound (I.9), or crystalline 12.50 12.50 12.50 5.00 5.00 5.00form (I.9X) of compound (I.9)) Lactose monohydrate 65.50 65.50 65.5081.25 81.25 81.25 Cellulose microcrystalline 25.00 25.00 25.00 31.2531.25 31.25 Hydroxypropylcellulose 3.00 3.00 3.00 3.75 3.75 3.75Croscarmellose sodium 2.00 2.00 2.00 2.50 2.50 2.50 Colloidal siliciumdioxide 0.50 0.50 0.50 0.025 0.625 0.625 Magnesium stearate 0.50 0.500.50 0.625 0.625 0.625 Metformin HCl-portion: (570) (969) (1140) (570)(969) (1140) Metformin Hydrochloride 500.0 850.00 1000.00 500.0 850.001000.00 Corn starch 15.00 25.50 30.00 15.00 25.50 30.00 Copovidone 47.5080.57 95.00 47.50 80.57 95.00 Colloidal Anhydrous Silica 2.50 4.25 5.002.50 4.25 5.00 Magnesium stearate 5.00 8.50 10.00 5.00 8.50 10.00 TotalMass (tablet core) 670 1069 1240 695 1094.00 1265.00 Hypromellose 29106.00 8.00 9.00 6.00 8.00 9.00 Propylene glycol 0.60 0.80 0.90 0.60 0.800.90 Talc 2.40 3.20 3.60 2.40 3.20 3.60 Titanium dioxide 2.76 3.68 4.142.76 3.68 4.14 Iron oxide, black 0.12 0.16 0.18 0.12 0.16 0.18 Ironoxide, red 0.12 0.16 0.18 0.12 0.16 0.18 Total Mass (film-coat) 12.0016.000 18.001 12.00 16.000 18.001 Total Mass (coated tablet) 682.001085.00 1258.01 707.00 1110.00 1283.01

A broad dose range of SGLT-2 inhibitor, eg. 1.25, 5 or 12.5 mg, could beused, in which case the amount of binder corn starch or microcrystallinecellulose is adjusted. Instead of corn starch, microcrystallinecellulose could be used. In the further description of the manufacturingprocedure only corn starch is described.

Manufacturing Procedure (Tablet-in-Tablet or Bull's Eye Tablet):

SGLT-2 inhibitor of this invention (e.g. compound (I.9), or crystallineform (I.9X) of compound (I.9))+metformin HCl FDC Tablet-in-Tablet orBull's eye tablets are produced by a high-shear wet granulation process(for SGLT-2 inhibitor-granulate), a rotary press (for SGLT-2 inhibitorcore-tablet), a fluid-bed granulation process (for metforminHCl-granulate), and press-coating process with a press-coater.

SGLT-2 inhibitor-granulate: By using a high-shear granulator the activeSGLT-2 inhibitor. The overall manufacturing process consisted offollowing steps:

1) Screen hydroxpropyl cellulose (HPC)

2) Add the intra-granular microcrystalline cellulose portion. SGLT-2inhibitor, lactose, HPC and croscarmelose sodium to the granulator

3) Granulate the blend with water.

4) Dry the granulate in Fluid bed drier: less than 1.5% LOD

5) Mill the granulation into the blender container

-   -   Quadro mill with screen—18 mesh.

6) Screen the following onto milled granulation in the container of atumble blender

-   -   Premix of the colloidal silicon dioxide with a portion of the        extra-granular microcrystalline cellulose screened through 20-25        mesh.    -   Remainder of the extra-granular microcrystalline cellulose and        blend.

7) Premix the magnesium stearate with a portion of the blendedgranulation, screen (18 mesh) onto the remainder of the granulation inthe blender.

Subsequently the “Final Blend” is produced by final blending in thefree-fall blender.

8.) The “Final Blend” of the SGLT-2 inhibitor is compressed into tabletswith a rotary press.

Metformin HCl-granulate: Metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. Alternatively, theSGLT-2 inhibitor is added as powder together with metformin-HCl and cornstarch to the fluid bed granulator. After finishing of fluid-bedgranulation, the granulate is sieved with a suitable screen. The sievedgranulate is blended with colloidal anhydrous silica (Aerosil 200) andmagnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

-   -   a) Metformin HCl is sieved using a screen with a mesh size of        0.5 to 1 mm before weighing.    -   b) Copolyvidon is dissolved in purified water at ambient        temperature with a propeller mixer to produce the “Granulation        Liquid”    -   d) The “Granulation Liquid” is sprayed into the mixture for        fluid-bed granulating under dry condition to avoid blocking        during granulation.    -   e) At the end of spraying, the resultant granulate is dried at        70-80 ° C. until the desired LOD value (i.e. 0.8-2%, for example        1-2%), in case the LOD is more than 2%.    -   f) The granulate is sieved using a screen with a mesh size of        0.5 to 1.0 mm.    -   g) The sieved granulate and colloidal anhydrous silica        (Aerosil 200) are blended with a suitable blender. Aerosil 200        should be sieved with a 0.5 mm-screen before use.    -   h) Magnesium stearate passed through a 0.5 mm sieve and added        into the granulate. Subsequently “Metformin HCl-granulate”        (Final Blend) is produced by final blending in the blender.

The “SGLT-2 inhibitor core-tablets” and “Metformin HCl-granulate” arecompressed into Tablet-in-Tablet or Bull's eye tablets using apress-coater. The difference between the Tablet-in-Tablet and Bull's eyetablet is the position of the core tablet.

Narrative more specific description of the manufacturing process for theTablet-in-Tablet:

-   -   a) Fill a half of Metformin HCl-granulate in a die.    -   b) Place a compound (I.9), or crystalline form (I.9X) of        compound (I.9)) core-tablet on the surface of Metformin        HCl-granulate.    -   c) Cover the core-tablet with second half of Metformin        HCl-granulate, then compressed into the tablet        (Tablet-in-Tablet).

Narrative more specific description of the manufacturing process for theBull's eye tablets:

-   -   a) Fill Metformin HCl-granulate in a die.    -   b) Place the compound (I.9), or crystalline form (I.9X) of        compound (I.9)) core-tablet on the Metformin HCl-granulate in        the die, then compressed into the tablet (Bull's eye tablet).

The tablets may be film-coated by an aqueous film-coating suspension,containing hypromellose as film-forming agent, polyethylene glycol orpropylene glycol as plasticizer, talc as glidant and the pigmentsyellow, red, black iron oxide and mixture thereof and titanium dioxide.

Narrative more specific description of the manufacturing process for thefilm-coating:

-   -   a) Hypromellose and polyethylene glycol or propylene glycol are        dissolved in purified water with a propeller mixer. Talc,        titanium dioxide, and iron oxide (yellow, red, black or mixture        thereof) are dispersed in purified water with a homo-mixer. The        suspension is added into the hypromellose solution, then mixed        with a propeller mixer at ambient temperature to produce the        “Coating Suspension”.    -   b) The tablet cores are coated with the “Coating Suspension” to        the target weight gain to produce the “Film-coated Tablets”. The        “Coating Suspension” should be stirred again before use and kept        stirring slowly during the coating (spraying) process.

4. SGLT-2 Inhibitor—Drug Layering on Metformin HCl Tablet (Film-Coatingfor Drug-Loading)

Examples of the composition of a SGLT-2 inhibitor of this invention(Compound (I.9), or crystalline form (I.9X) of compound (I.9))+metforminHCl FDC (Film-coated Tablets) which are prepared by drug loading byfilm-coating on the Metformin HCl Tablet is shown in Table 4.

TABLE 4 Examples of the composition of Compound (I.9), or crystallineform (I.9X) of compound (I.9)) + Metformin HCl FDC SGLT-2inhibitor-Coating on Metformin HCl Tablet Dose Strength (SGLT-2inhibitor/ metformin HCl), mg 12.5/500 12.5/850 12.5/1000 Ingredient[mg] [mg] [mg] Metformin HCl-portion: (570)    (969)    (1140)   Metformin Hydrochloride 500.0   850.0   1000.0   Corn starch 15.0  25.5 30.0  Copovidone 47.5  80.57  95.0  Colloidal Anhydrous 2.5  4.25 5.0 Silica Magnesium stearate 5.0  8.5  10.0  Total Mass (tablet core)570    969    1140    Seal-coat (seal-coating): (12)   (16)   (18)  Hypromellose 2910 6.00 8.00 9.00 Propylene glycol 0.60 0.80 0.90 Talc2.22 2.96 3.33 Titanium dioxide 3.00 4.00 4.50 Iron oxide, black 0.150.20  0.225 Iron oxide, red 0.03 0.04  0.045 Drug-layer (drug-loading):(32.5)  (32.5)  (32.5)  Compound (I.9), or 12.50  12.50  12.50 crystalline form (I.9X) of compound (I.9)) Hypromellose 2910 18.00 18.00  18.00  Propylene glycol 2.00 2.00 2.00 Over-coat (over-coating):(12)   (16)   (18)   Hypromellose 2910 6.00 8.00 9.00 Propylene glycol0.60 0.80 0.90 Talc 2.22 2.96 3.33 Titanium dioxide 3.00 4.00 4.50 Ironoxide, black 0.15 0.20  0.225 Iron oxide, red 0.03 0.04  0.045 TotalMass (film-coat) 44.5  48.5  50.5  Total Mass (coated tablet) 614.5  1017.5   1190.5  

A broad dose range of SGLT-2 inhibitor, eg. 1.25, 5 or 12.5 mg, could beused, in which case the amount of binder corn starch or microcrystallinecellulose is adjusted. Instead of corn starch, microcrystallinecellulose could be used. In the further description of the manufacturingprocedure only corn starch is described.

Manufacturing Procedure (SGLT-2 Inhibitor-Drug Layering by Film-Coatingon Metformin HCl Tablet):

SGLT-2 inhibitor (e.g. Compound (I.9), or crystalline form (I.9X) ofcompound (I.9))+metformin HCl FDC with drug coating is produced by afluid-bed granulation process, a conventional tableting process, andfilm-coating process with three steps: seal-coating, drug-loading andover-coating. The over-coating may be able to be skipped by combiningwith the drug-loading, if the stability is acceptable.

Metformin HCl Tablets: Metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. Alternatively, theSGLT-2 inhibitor is added as powder together with metfomin-HCl and cornstarch to the fluid bed granulator. After finishing of fluid-bedgranulation, the granulate is sieved with a suitable screen. The sievedgranulate is blended with colloidal anhydrous silica (Aerosil 200) andmagnesium stearate as a lubricant. The final blend is compressed intothe tablets with a conventional rotary press.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

-   -   a) Metformin HCl is sieved using a screen with a mesh size of        0.5 to 1 mm before weighing.    -   b) Copolyvidon is dissolved in purified water at ambient        temperature with a propeller mixer to produce the “Granulation        Liquid”    -   d) The “Granulation Liquid” is sprayed into the mixture for        fluid-bed granulating under dry condition to avoid blocking        during granulation.    -   e) At the end of spraying, the resultant granulate is dried at        70-80 ° C. until the desired LOD value (i.e. 0.8-2%, for example        1-2%), in case the LOD is more than 2%.    -   f) The granulate is sieved using a screen with a mesh size of        0.5 to 1.0 mm.    -   g) The sieved granulate and colloidal anhydrous silica        (Aerosil 200) are blended with a suitable blender. Aerosil 200        should be sieved with a 0.5 mm-screen before use.    -   h) Magnesium stearate passed through a 0.5 mm sieve and added        into the granulate. Subsequently “Final Blend” is produced by        final blending in the blender.    -   i) The “Final Blend” is compressed into the tablets with a        conventional rotary press.

Film-coating: The tablets are film-coated by (1) seal-coating: by anaqueous film-coating suspension, containing hypromellose as film-formingagent, polyethylene glycol (Macrogol, especially Macrogol 400, 6000 or8000) as plasticizer, propylene glycol as alternative plasticizer, talcas glidant and the pigments yellow iron oxide and/or red iron oxide ormixtures with iron oxide black and titanium dioxide, (2) drug-loading:by an aqueous film-coating suspension, containing hypromellose asfilm-forming agent, polyethylene glycol or propylene glycol asplasticizer, compound (I.9), or crystalline form (I.9X) of compound(I.9) as drug substance and (3) over-coating: by an aqueous film-coatingsuspension, containing hypromellose as film-forming agent, polyethyleneglycol or propylene glycol as plasticizer, talc as glidant and thepigments yellow iron oxide and/or red and/or black iron oxide andtitanium dioxide,

Narrative more specific description of the manufacturing process for thefilm-coating with a coating machine:

-   -   a) Hypromellose and polyethylene glycol or propylene glycol are        dissolved in purified water with a propeller mixer. Talc,        titanium dioxide, and iron oxide (yellow, red, black or yellow        and red and black and mixture thereof) are dispersed in purified        water with a homo-mixer. The suspension is added into the        hypromellose solution, then mixed with a propeller mixer at        ambient temperature to produce the “Coating Suspension” for        “seal-coating” and “over-coating”.    -   b) Hypromellose, polyethylene glycol or propylene glycol are        dissolved in purified water with a propeller mixer. Compound        (I.9), or crystalline form (I.9X) of compound (I.9) (active        drug) is added into the hypromellose solution, then dispersed        with a propeller mixer at ambient temperature to produce the        “Drug Suspension” for “drug-loading”.    -   c) The Metformin HCl tablets are coated with the “Coating        Suspension” to the target weight gain to form the “seal-coat”.        The “Coating Suspension” should be stirred again before use and        kept stirring slowly during the coating (spraying) process.    -   d) Following the seal-coating, the “Drug Suspension” is applied        to the surface of the Metformin HCl tablets to form the “drug        layer” (drug loading). The “Drug Suspension” should be stirred        again before use and kept stirring slowly during the coating        (spraying) process. The coating end point can be determined by        available PAT (Process Analysis Technology).    -   e) After drug loading the “Coating Suspension” is applied to the        compound (I.9), or crystalline form (I.9X) of compound (I.9)        drug-loaded tablets to form the “over-coat” and to produce the        “Film-coated Tablets”. The “Coating Suspension” should be        stirred again before use and kept stirring slowly during the        coating (spraying) process.

Product Description:

The product description of Compound (I.9), or crystalline form (I.9X) ofcompound (I.9)+Metformin HCl FDC mono-layer tablets (tablet core andfilm-coated tablets) is shown in Table 8 and Table 9, respectively.

TABLE 8a Product Description of Compound (I.9), or crystalline form(I.9X) of compound (I.9) + Metformin HCl FDC Mono-layer Tablets (TabletCore) Dose Strength (SGLT-2 inhibitor/ metformin HCl), mg 5 or 5 or 5 orItems 12.5/500 12.5/850 12.5/1000 Tablet shape Oval, Oval, Oval,biconvex biconvex biconvex Core tablet size [mm] 16.2 × 8.5 19.1 × 9.321.0 × 9.6 Color white Weight 590 1000 1180 Crushing strength [N],(Mean) ≥100 ≥150 ≥150 Disintegration time [min] ≤15 ≤15 ≤15 Friability[%] ≤0.5 ≤0.5 ≤0.5

TABLE 8b Product Description of Compound (I.9), or crystalline form(I.9X) of compound (I.9) + Metformin HCl FDC Mono-layer Tablets (TabletCore) Dose Strength (SGLT-2 inhibitor/ metformin HCl), mg 5 or 5 or 5 orItems 12.5/500 12.5/850 12.5/1000 Tablet shape Oval, Oval, Oval,biconvex biconvex biconvex Core tablet size [mm] 16.2 × 8.5 19.1 × 9.321.0 × 9.6 Color white Weight 590 1003 1180 Crushing strength [N],(Mean) ≥100 ≥150 ≥150 Disintegration time [min] ≤15 ≤15 ≤15 Friability[%] ≤0.5 ≤0.5 ≤0.5

TABLE 9a Product Description of Compound (I.9), or crystalline form(I.9X) of compound (I.9) + Metformin HCl FDC Mono-layer Tablets (Coated)Dose Strength (SGLT-2/ metformin HCl), mg 5 or 5 or 5 or Items 12.5/50012.5/850 12.5/1000 Color yellow/red/ yellow/red/ yellow/red/ black blackblack mixtures or mixtures or mixtures or red/black red/black red/blackmixtures mixtures mixtures Weight 602 1016 1198 Crushing strength [N](Mean) ≥120 ≥160 ≥160 Disintegration time [min] ≤15 ≤15 ≤15

TABLE 9b Product Description of Compound (I.9), or crystalline form(I.9X) of compound (I.9) + Metformin HCl FDC Mono-layer Tablets (Coated)Dose Strength (SGLT-2/ metformin HCl), mg 5 or 5 or 5 or Items 12.5/50012.5/850 12.5/1000 Color red/black red/black red/black mixtures mixturesmixtures Weight 602 1020 1199 Crushing strength [N] (Mean) ≥120 ≥160≥160 Disintegration time [min] ≤15 ≤15 ≤15

Stability Data:

Stability data of Compound (I.9), or crystalline form (I.9X) of compound(I.9)+Metformin HCl FDC mono-layer tablets (Table 1.1 and 1.7) is shownin the following tables.

12.5 + 500 mg tablets Test parameter 60° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2

12.5 + 500 mg tablets Test parameter 40° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

12.5 + 500 mg tablets Test parameter 40° C. glass bottle, open Initial 8W Degradation compound (I.9), <0.2 or crystalline form (I.9X) ofcompound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

12.5 + 500 mg tablets Test parameter 60° C. glass bottle, with NaCLInitial 8 W Degradation compound (I.9), 1.0 or crystalline form (I.9X)of compound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.21.0

1.25 + 500 mg tablets Test parameter 60° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2

1.25 + 500 mg tablets Test parameter 40° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

1.25 + 500 mg tablets Test parameter 40° C. glass bottle, open Initial 8W Degradation compound (I.9), <0.2 or crystalline form (I.9X) ofcompound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

1.25 + 500 mg tablets Test parameter 60° C. glass bottle, with NaCLInitial 8 W Degradation compound (I.9), 1.0 or crystalline form (I.9X)of compound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.21.0

Stability Data:

Stability data of Compound (I.9), or crystalline form (I.9X) of compound(I.9)+Metformin HCl FDC mono-layer tablets (Table 1.9 and 1.10) is shownin the following tables.

12.5 + 500 mg tablets Test parameter 60° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2

12.5 + 500 mg tablets Test parameter 40° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

12.5 + 500 mg tablets Test parameter 40° C. glass bottle, open Initial 8W Degradation compound (I.9), <0.2 or crystalline form (I.9X) ofcompound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

12.5 + 500 mg tablets Test parameter 60° C. glass bottle, with NaCLInitial 8 W Degradation compound (I.9), 1.3 or crystalline form (I.9X)of compound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.21.3

1.25 + 500 mg tablets Test parameter 60° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2

1.25 + 500 mg tablets Test parameter 40° C. glass bottle Initial 8 WDegradation compound (I.9), <0.2 or crystalline form (I.9X) of compound(I.9) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

1.25 + 500 mg tablets Test parameter 40° C. glass bottle, open Initial 8W Degradation compound (I.9), <0.2 or crystalline form (I.9X) ofcompound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.2 <0.2

1.25 + 500 mg tablets Test parameter 60° C. glass bottle, with NaCLInitial 8 W Degradation compound (I.9), 1.6 or crystalline form (I.9X)of compound (I.9)) (%) Degradation Metformin (%) <0.2 <0.2 Total <0.21.6

1-23. (canceled)
 24. Method for preventing, slowing the progression of,delaying or treating a metabolic disorder selected from the groupconsisting of type 1 diabetes mellitus, type 2 diabetes mellitus,impaired glucose tolerance, impaired fasting blood glucose,hyperglycemia, postprandial hyperglycemia, overweight, obesity andmetabolic syndrome comprising administering to a patient in need thereofa pharmaceutical composition comprising a SGLT-2 inhibitor, a partnerdrug, and one or more pharmaceutical excipients or a pharmaceuticaldosage form comprising said pharmaceutical composition.
 25. Method forimproving glycemic control and/or for reducing of fasting plasmaglucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c comprising administering to a patient in need thereof apharmaceutical composition comprising a SGLT-2 inhibitor, a partnerdrug, and one or more pharmaceutical excipients or a pharmaceuticaldosage form comprising said pharmaceutical composition.
 26. Method forpreventing, slowing, delaying or reversing progression from impairedglucose tolerance, impaired fasting blood glucose, insulin resistanceand/or from metabolic syndrome to type 2 diabetes mellitus comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising a SGLT-2 inhibitor, a partner drug, and one or morepharmaceutical excipients or a pharmaceutical dosage form comprisingsaid pharmaceutical composition.
 27. Method for preventing, slowing theprogression of, delaying or treating of a condition or disorder selectedfrom the group consisting of complications of diabetes mellitus such ascataracts and micro- and macrovascular diseases, such as nephropathy,retinopathy, neuropathy, tissue ischaemia, diabetic foot,arteriosclerosis, myocardial infarction, accute coronary syndrome,unstable angina pectoris, stable angina pectoris, stroke, peripheralarterial occlusive disease, cardiomyopathy, heart failure, heart rhythmdisorders and vascular restenosis, comprising administering to a patientin need thereof a pharmaceutical composition comprising a SGLT-2inhibitor, a partner drug, and one or more pharmaceutical excipients ora pharmaceutical dosage form comprising said pharmaceutical composition.28. Method for reducing body weight or preventing an increase in bodyweight or facilitating a reduction in body weight comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising a SGLT-2 inhibitor, a partner drug, and one or morepharmaceutical excipients or a pharmaceutical dosage form comprisingsaid pharmaceutical composition.
 29. Method for preventing, slowing,delaying or treating the degeneration of pancreatic beta cells and/orthe decline of the functionality of pancreatic beta cells and/or forimproving and/or restoring the functionality of pancreatic beta cellsand/or restoring the functionality of pancreatic insulin secretioncomprising administering to a patient in need thereof a pharmaceuticalcomposition comprising a SGLT-2 inhibitor, a partner drug, and one ormore pharmaceutical excipients or a pharmaceutical dosage formcomprising said pharmaceutical composition.
 30. Method for preventing,slowing, delaying or treating diseases or conditions attributed to anabnormal accumulation of liver fat comprising administering to a patientin need thereof a pharmaceutical composition comprising a SGLT-2inhibitor, a partner drug, and one or more pharmaceutical excipients ora pharmaceutical dosage form comprising said pharmaceutical composition.31. Method for maintaining and/or improving the insulin sensitivityand/or for treating or preventing hyperinsulinemia and/or insulinresistance comprising administering to a patient in need thereof apharmaceutical composition comprising a SGLT-2 inhibitor, a partnerdrug, and one or more pharmaceutical excipients or a pharmaceuticaldosage form comprising said pharmaceutical composition.
 32. Methodaccording to claim 24, wherein the patient is an individual diagnosed ofone or more of the conditions selected from the group consisting ofoverweight, obesity, visceral obesity and abdominal obesity.
 33. Methodaccording to claim 24, wherein the patient is an individual who showsone, two or more of the following conditions: (a) a fasting bloodglucose or serum glucose concentration greater than 110 mg/dL, inparticular greater than 125 mg/dL; (b) a postprandial plasma glucoseequal to or greater than 140 mg/dL; (c) an HbA1c value equal to orgreater than 6.5%, in particular equal to or greater than 7.0%. 34.Method according to claim 24, wherein the patient is an individualwherein one, two, three or more of the following conditions are present:(a) obesity, visceral obesity and/or abdominal obesity, (b) triglycerideblood level ≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL infemale patients and <50 mg/dL in male patients, (d) a systolic bloodpressure ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, (e) afasting blood glucose level ≥110 mg/dL.
 35. Method according to claim24, wherein the patient has insufficient glycemic control despite dietand exercise or despite monotherapy with an antidiabetic agent, inparticular with metformin.